Hugues Allard-Chamard et al.

Extrafollicular IgD−CD27−CXCR5−CD11c− DN3 B cells infiltrate inflamed tissues in autoimmune fibrosis and in severe COVID-19

Cell, May 2023; doi.org/10.1016/j.celrep.2023.112630

Abstract

Although therapeutic B cell depletion dramatically resolves inflammation in many diseases in which antibodies appear not to play a central role, distinct extrafollicular pathogenic B cell subsets that accumulate in disease lesions have hitherto not been identified. The circulating immunoglobulin D (IgD)−CD27−CXCR5−CD11c+ DN2 B cell subset has been previously studied in some autoimmune diseases. A distinct IgD−CD27−CXCR5−CD11c− DN3 B cell subset accumulates in the blood both in IgG4-related disease, an autoimmune disease in which inflammation and fibrosis can be reversed by B cell depletion, and in severe COVID-19. These DN3 B cells prominently accumulate in the end organs of IgG4-related disease and in lung lesions in COVID-19, and double-negative B cells prominently cluster with CD4+ T cells in these lesions. Extrafollicular DN3 B cells may participate in tissue inflammation and fibrosis in autoimmune fibrotic diseases, as well as in COVID-19.

Luca Schifanella et al.

The Defenders of the Alveolus Succumb in COVID-19 Pneumonia to SARS-CoV-2 and Necroptosis, Pyroptosis, and PANoptosis

Academic.oup; Marc 2023; doi.org/10.1093/infdis/jiad056

Abstract

Alveolar type II (ATII) pneumocytes as defenders of the alveolus are critical to repairing lung injury. We investigated the ATII reparative response in coronavirus disease 2019 (COVID-19) pneumonia, because the initial proliferation of ATII cells in this reparative process should provide large numbers of target cells to amplify severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus production and cytopathological effects to compromise lung repair. We show that both infected and uninfected ATII cells succumb to tumor necrosis factor-α (TNF)-induced necroptosis, Bruton tyrosine kinase (BTK)-induced pyroptosis, and a new PANoptotic hybrid form of inflammatory cell death mediated by a PANoptosomal latticework that generates distinctive COVID-19 pathologies in contiguous ATII cells. Identifying TNF and BTK as the initiators of programmed cell death and SARS-CoV-2 cytopathic effects provides a rationale for early antiviral treatment combined with inhibitors of TNF and BTK to preserve ATII cell populations, reduce programmed cell death and associated hyperinflammation, and restore functioning alveoli in COVID-19 pneumonia.

Lawrence O. Gostin and Gigi K. Gronvall

The Origins of Covid-19 — Why It Matters (and Why It Doesn’t)

NEJM, June 2023; doi/full/10.1056/NEJMp2305081?query=featured_home

Abstract

When health emergencies arise, scientists seek to discover the cause — such as how a pathogen emerged and spread — because this knowledge can enhance our understanding of risks and strategies for prevention, preparedness, and mitigation. Yet well into the fourth year of the Covid-19 pandemic, intense political and scientific debates about its origins continue. The two major hypotheses are a natural zoonotic spillover, most likely occurring at the Huanan Seafood Wholesale Market, and a laboratory leak from the Wuhan Institute of Virology (WIV). It is worth examining the efforts to discover the origins of SARS-CoV-2, the political obstacles, and what the evidence tells us. This evidence can help clarify the virus’s evolutionary path. But regardless of the origins of the virus, there are steps the global community can take to reduce future pandemic threats.

Key Events in the Effort to Determine the Origins of the Covid-19 Pandemic.

The origins story dates back to December 31, 2019, when the World Health Organization (WHO) learned of a cluster of cases of pneumonia of unknown cause in Wuhan (see timeline). Wuhan authorities closed the Huanan market the next day, rendering live animals unavailable for testing. China publicly shared the SARS-CoV-2 genetic sequence on January 10, 2020. It was not until weeks after the WHO declared Covid-19 a Public Health Emergency of International Concern on January 30 that the WHO–China Joint Mission visited Beijing and Wuhan (February 16 to February 24).

The joint WHO–China technical report published in March 2021 rated a zoonotic spillover as a “likely to very likely” source of the virus, cold food–chain products as “possible,” and a laboratory incident as “extremely unlikely.”1 The WHO director-general immediately repudiated the report’s findings, believing it was premature to rule out a possible laboratory incident. An open letter published in Science on May 14, 2021, credited the laboratory theory, calling for open access to laboratory records and science-based studies.2 On October 13, 2021, the WHO director-general established the Scientific Advisory Group for the Origins of Novel Pathogens (SAGO). China officially rejected the WHO’s plan for a second phase of investigation of origins. The SAGO’s preliminary report warned that China was withholding key data.

Recently, a team of international experts announced that they had identified data on SARS-CoV-2–positive environmental samples collected from the Huanan market in January 2020, which China had withheld from the public domain for 3 years. Chinese scientists had uploaded the data to GISAID (the Global Initiative on Sharing All Influenza Data) but then removed them. In response to pressure from the WHO, China restored those data to GISAID.

Determining the origins of SARS-CoV-2 should be strictly a scientific matter, but it has become embroiled in politics. In March 2020, the Chinese Ministry of Foreign Affairs alleged, without evidence, that U.S. Army personnel had introduced SARS-CoV-2 during a visit to Wuhan, prompting President Donald Trump to claim that the virus originated at the WIV. Accusing the director-general of siding with China, Trump notified the United Nations that the United States intended to withdraw from the WHO. Although President Joe Biden later reversed that decision, the origins controversy has continued. On May 26, 2021, Biden ordered U.S. intelligence agencies to review the competing origins hypotheses. The Office of the Director of National Intelligence released the “Declassified Assessment on COVID-19 Origins,” finding that the evidence to support either of the two plausible theories was inconclusive and acknowledging that China’s cooperation was necessary for reaching any conclusive assessment.

Origins politics heated up early this year. On January 25, 2023, the Office of the Inspector General of the Department of Health and Human Services concluded that the National Institute of Allergy and Infectious Diseases had failed to adequately oversee a grant to the EcoHealth Alliance for research into bat viruses at the WIV.4 A month later, the Department of Energy, which oversees a network of 17 U.S. laboratories, concluded with “low confidence” that SARS-CoV-2 most likely arose from a laboratory incident. The Federal Bureau of Investigation said it favored the laboratory theory with “moderate” confidence. Four other agencies, along with a national intelligence panel, still judge that SARS-CoV-2 emerged from natural zoonotic spillover, while two remain undecided. All U.S. intelligence agencies rejected the allegation that participants in a clandestine Chinese biologic weapons program intentionally developed SARS-CoV-2. Yet a report issued in mid-December 2022 by Republican members of the House of Representatives still credited that theory. On March 20, 2023, Biden signed a bill declassifying documents about Covid-19’s origins, and Congress commenced hearings.

Of the three possibilities — natural, accidental, or deliberate — the most scientific evidence yet identified supports natural emergence. More than half of the earliest Covid-19 cases were connected to the Huanan market, and epidemiologic mapping revealed that the concentration of cases was centered there. In January 2020, Chinese officials cleared the market without testing live animals, but positive environmental samples, including those from an animal cage and a hair-and-feather–removal machine, indicated the presence of both SARS-CoV-2 and Covid-susceptible animals.5 Recently released findings included raccoon dog DNA, pointing to a possible SARS-CoV-2 progenitor. Samples from early cases in humans also contained two different SARS-CoV-2 lineages. Although only one lineage spread globally, the existence of multiple lineages suggests that a SARS-CoV-2 epidemic in animals may have led to multiple spillover events.

Proponents of the accidental laboratory leak theory stress the geographic location of the WIV in the city where the pandemic began. They point to the presence of the bat coronavirus RaTG13 strain at the laboratory, arguing that genetic manipulations such as gain-of-function (GOF) research may have produced SARS-CoV-2. Most scientists refute this theory because there is considerable evolutionary distance between the two viruses. However, the possibility that the laboratory held a different progenitor strain to SARS-CoV-2 that led to a laboratory leak cannot be unequivocally ruled out.

China’s obfuscation may mean that we will never have certainty about the origins of the greatest pandemic in more than a century. After all the world has suffered in loss of life, economic hardship, and exacerbated health disparities, there is intrinsic value in knowing the cause. An objectively determined body of scientific facts cannot fully defuse the political rhetoric surrounding the origins investigation, but the search must continue. The newly released genetic data may reveal whether specific animals were infected and offer information about where they came from, opening new possibilities to investigate, which may also improve attribution techniques for investigating future outbreaks. Irrespective of Covid’s origins, future outbreaks could result from deliberate, accidental, or natural causes, and improving our ability to understand and prove theories will be critical. We propose three important steps for fortifying pandemic preparedness.

First, preventing spillovers by using a One Health strategy linking animal, human, and environmental health is vital. Some 60% of outbreaks of diseases previously unseen in humans arise from natural zoonoses. Human and animal populations could be separated more effectively with stricter regulation of wet markets and enforcement of laws prohibiting wildlife trade. Land-management efforts such as halting deforestation would benefit the environment while creating a buffer between wildlife and humans. Widespread use of sustainable and humane farming practices would eliminate overcrowding of domesticated animals and curtail prophylactic antimicrobial use — with added benefits in preventing antimicrobial resistance.

Second, it is important to fortify laboratory safety to reduce the risks of unintentional release of a dangerous pathogen. Regulatory requirements should include site-specific and activity-specific risk assessments to identify and mitigate risks; core protocols for infection prevention and control; and training for proper use of, and access to, personal protective equipment. International standards exist for biorisk management, which should be broadly adopted.

Third, GOF research designed to elucidate the transmissibility or pathogenicity traits of pathogens should be appropriately overseen to reduce risks while allowing important research and vaccine development to continue. Such research may result in the creation of microbes with enhanced pandemic potential, which could be released unintentionally or intentionally. However, there is no international agreement about which research activities are problematic or how to reduce risks. On January 27, 2023, the U.S. National Science Advisory Board for Biosecurity issued a more rigorous framework for oversight of research, which prominent virologists criticized as overbroad and inhibitory to U.S. vaccine development. Since GOF research is conducted in laboratories globally, an international framework is needed.

Since the pandemic’s earliest days, controversy has swirled about how it began. Origins investigations are scientific endeavors, but we need to plan ahead so that scientists get rapid access to key geographic sites, open scientific exchange, and full transparency. Though such investigations proceed more slowly than the news cycle, these steps are the keys to unlocking the mystery surrounding Covid-19 and preparing the world for the future outbreaks that are certain to occur.

Lawrence O. Gostin and Gigi K. Gronvall

The Origins of Covid-19 — Why It Matters (and Why It Doesn’t)

NEJM, June 2023; doi/full/10.1056/NEJMp2305081?query=featured_home

Abstract

When health emergencies arise, scientists seek to discover the cause — such as how a pathogen emerged and spread — because this knowledge can enhance our understanding of risks and strategies for prevention, preparedness, and mitigation. Yet well into the fourth year of the Covid-19 pandemic, intense political and scientific debates about its origins continue. The two major hypotheses are a natural zoonotic spillover, most likely occurring at the Huanan Seafood Wholesale Market, and a laboratory leak from the Wuhan Institute of Virology (WIV). It is worth examining the efforts to discover the origins of SARS-CoV-2, the political obstacles, and what the evidence tells us. This evidence can help clarify the virus’s evolutionary path. But regardless of the origins of the virus, there are steps the global community can take to reduce future pandemic threats.

Key Events in the Effort to Determine the Origins of the Covid-19 Pandemic.

The origins story dates back to December 31, 2019, when the World Health Organization (WHO) learned of a cluster of cases of pneumonia of unknown cause in Wuhan (see timeline). Wuhan authorities closed the Huanan market the next day, rendering live animals unavailable for testing. China publicly shared the SARS-CoV-2 genetic sequence on January 10, 2020. It was not until weeks after the WHO declared Covid-19 a Public Health Emergency of International Concern on January 30 that the WHO–China Joint Mission visited Beijing and Wuhan (February 16 to February 24).

The joint WHO–China technical report published in March 2021 rated a zoonotic spillover as a “likely to very likely” source of the virus, cold food–chain products as “possible,” and a laboratory incident as “extremely unlikely.”1 The WHO director-general immediately repudiated the report’s findings, believing it was premature to rule out a possible laboratory incident. An open letter published in Science on May 14, 2021, credited the laboratory theory, calling for open access to laboratory records and science-based studies.2 On October 13, 2021, the WHO director-general established the Scientific Advisory Group for the Origins of Novel Pathogens (SAGO). China officially rejected the WHO’s plan for a second phase of investigation of origins. The SAGO’s preliminary report warned that China was withholding key data.

Recently, a team of international experts announced that they had identified data on SARS-CoV-2–positive environmental samples collected from the Huanan market in January 2020, which China had withheld from the public domain for 3 years. Chinese scientists had uploaded the data to GISAID (the Global Initiative on Sharing All Influenza Data) but then removed them. In response to pressure from the WHO, China restored those data to GISAID.

Determining the origins of SARS-CoV-2 should be strictly a scientific matter, but it has become embroiled in politics. In March 2020, the Chinese Ministry of Foreign Affairs alleged, without evidence, that U.S. Army personnel had introduced SARS-CoV-2 during a visit to Wuhan, prompting President Donald Trump to claim that the virus originated at the WIV. Accusing the director-general of siding with China, Trump notified the United Nations that the United States intended to withdraw from the WHO. Although President Joe Biden later reversed that decision, the origins controversy has continued. On May 26, 2021, Biden ordered U.S. intelligence agencies to review the competing origins hypotheses. The Office of the Director of National Intelligence released the “Declassified Assessment on COVID-19 Origins,” finding that the evidence to support either of the two plausible theories was inconclusive and acknowledging that China’s cooperation was necessary for reaching any conclusive assessment.

Origins politics heated up early this year. On January 25, 2023, the Office of the Inspector General of the Department of Health and Human Services concluded that the National Institute of Allergy and Infectious Diseases had failed to adequately oversee a grant to the EcoHealth Alliance for research into bat viruses at the WIV.4 A month later, the Department of Energy, which oversees a network of 17 U.S. laboratories, concluded with “low confidence” that SARS-CoV-2 most likely arose from a laboratory incident. The Federal Bureau of Investigation said it favored the laboratory theory with “moderate” confidence. Four other agencies, along with a national intelligence panel, still judge that SARS-CoV-2 emerged from natural zoonotic spillover, while two remain undecided. All U.S. intelligence agencies rejected the allegation that participants in a clandestine Chinese biologic weapons program intentionally developed SARS-CoV-2. Yet a report issued in mid-December 2022 by Republican members of the House of Representatives still credited that theory. On March 20, 2023, Biden signed a bill declassifying documents about Covid-19’s origins, and Congress commenced hearings.

Of the three possibilities — natural, accidental, or deliberate — the most scientific evidence yet identified supports natural emergence. More than half of the earliest Covid-19 cases were connected to the Huanan market, and epidemiologic mapping revealed that the concentration of cases was centered there. In January 2020, Chinese officials cleared the market without testing live animals, but positive environmental samples, including those from an animal cage and a hair-and-feather–removal machine, indicated the presence of both SARS-CoV-2 and Covid-susceptible animals.5 Recently released findings included raccoon dog DNA, pointing to a possible SARS-CoV-2 progenitor. Samples from early cases in humans also contained two different SARS-CoV-2 lineages. Although only one lineage spread globally, the existence of multiple lineages suggests that a SARS-CoV-2 epidemic in animals may have led to multiple spillover events.

Proponents of the accidental laboratory leak theory stress the geographic location of the WIV in the city where the pandemic began. They point to the presence of the bat coronavirus RaTG13 strain at the laboratory, arguing that genetic manipulations such as gain-of-function (GOF) research may have produced SARS-CoV-2. Most scientists refute this theory because there is considerable evolutionary distance between the two viruses. However, the possibility that the laboratory held a different progenitor strain to SARS-CoV-2 that led to a laboratory leak cannot be unequivocally ruled out.

China’s obfuscation may mean that we will never have certainty about the origins of the greatest pandemic in more than a century. After all the world has suffered in loss of life, economic hardship, and exacerbated health disparities, there is intrinsic value in knowing the cause. An objectively determined body of scientific facts cannot fully defuse the political rhetoric surrounding the origins investigation, but the search must continue. The newly released genetic data may reveal whether specific animals were infected and offer information about where they came from, opening new possibilities to investigate, which may also improve attribution techniques for investigating future outbreaks. Irrespective of Covid’s origins, future outbreaks could result from deliberate, accidental, or natural causes, and improving our ability to understand and prove theories will be critical. We propose three important steps for fortifying pandemic preparedness.

First, preventing spillovers by using a One Health strategy linking animal, human, and environmental health is vital. Some 60% of outbreaks of diseases previously unseen in humans arise from natural zoonoses. Human and animal populations could be separated more effectively with stricter regulation of wet markets and enforcement of laws prohibiting wildlife trade. Land-management efforts such as halting deforestation would benefit the environment while creating a buffer between wildlife and humans. Widespread use of sustainable and humane farming practices would eliminate overcrowding of domesticated animals and curtail prophylactic antimicrobial use — with added benefits in preventing antimicrobial resistance.

Second, it is important to fortify laboratory safety to reduce the risks of unintentional release of a dangerous pathogen. Regulatory requirements should include site-specific and activity-specific risk assessments to identify and mitigate risks; core protocols for infection prevention and control; and training for proper use of, and access to, personal protective equipment. International standards exist for biorisk management, which should be broadly adopted.

Third, GOF research designed to elucidate the transmissibility or pathogenicity traits of pathogens should be appropriately overseen to reduce risks while allowing important research and vaccine development to continue. Such research may result in the creation of microbes with enhanced pandemic potential, which could be released unintentionally or intentionally. However, there is no international agreement about which research activities are problematic or how to reduce risks. On January 27, 2023, the U.S. National Science Advisory Board for Biosecurity issued a more rigorous framework for oversight of research, which prominent virologists criticized as overbroad and inhibitory to U.S. vaccine development. Since GOF research is conducted in laboratories globally, an international framework is needed.

Since the pandemic’s earliest days, controversy has swirled about how it began. Origins investigations are scientific endeavors, but we need to plan ahead so that scientists get rapid access to key geographic sites, open scientific exchange, and full transparency. Though such investigations proceed more slowly than the news cycle, these steps are the keys to unlocking the mystery surrounding Covid-19 and preparing the world for the future outbreaks that are certain to occur.

Amesh Adalja et al.

How Infectious Disease Experts Impacted the Coronavirus Disease 2019 Response: Lessons From the Front Lines

CID, April 2023; doi.org/10.1093/cid/ciad137

Abstract

In this article, we summarize findings from research conducted by the Johns Hopkins Center for Health Security and the Infectious Diseases Society of America to understand infectious disease (ID) workforce contributions to the coronavirus disease 2019 (COVID-19) response and their impacts. ID experts were found to have made diverse and unique contributions that went well beyond their usual responsibilities, with many spending several hours a week on these activities without additional compensation. These efforts were thought to not only build community resilience but also augment the ongoing public health response. Respondents also reported several hospital and clinical leadership roles taken on during the pandemic, such as developing protocols and leading clinical trials. We also make several policy recommendations, such as medical student debt relief and improved compensation, that will be needed to help fortify the ID workforce for future pandemics.

Martina Milighetti et al

Large clones of pre-existing T cells drive early immunity against SARS-COV-2 and LCMV infection

Cell, May 2023; doi.org/10.1016/j.isci.2023.106937

Abstract

T cell responses precede antibody and may provide early control of infection. We analyzed the clonal basis of this rapid response following SARS-COV-2 infection. We applied T cell receptor (TCR) sequencing to define the trajectories of individual T cell clones immediately. In SARS-COV-2 PCR+ individuals, a wave of TCRs strongly but transiently expand, frequently peaking the same week as the first positive PCR test. These expanding TCR CDR3s were enriched for sequences functionally annotated as SARS-COV-2 specific. Epitopes recognized by the expanding TCRs were highly conserved between SARS-COV-2 strains but not with circulating human coronaviruses. Many expanding CDR3s were present at high frequency in pre-pandemic repertoires. Early response TCRs specific for lymphocytic choriomeningitis virus epitopes were also found at high frequency in the preinfection naive repertoire. High-frequency naive precursors may allow the T cell response to respond rapidly during the crucial early phases of acute viral infection.

Xiaosheng Wu et al

Secreted ORF8 induces monocytic pro-inflammatory cytokines through NLRP3 pathways in severe patients with COVID-19

Cell, May 2023; doi.org/10.1016/j.isci.2023.106929

Abstract

Despite extensive research, the specific factor associated with SARS-CoV-2 infection that mediates the life-threatening inflammatory cytokine response in patients with severe COVID-19 remains unidentified. Herein we demonstrate that the virus-encoded Open Reading Frame 8 (ORF8) protein is abundantly secreted as a glycoprotein in vitro and in symptomatic patients with COVID-19. ORF8 specifically binds to the NOD-like receptor family pyrin domain-containing 3 (NLRP3) in CD14+ monocytes to induce inflammasomal cytokine/chemokine responses including IL1β, IL8, and CCL2. Levels of ORF8 protein in the blood correlate with severity and disease-specific mortality in patients with acute SARS-CoV-2 infection. Furthermore, the ORF8-induced inflammasome response was readily inhibited by the NLRP3 inhibitor MCC950 in vitro. Our study identifies a dominant cause of pathogenesis, its underlying mechanism, and a potential new treatment strategy for severe COVID-19.

MariosKoutsakos, Ali H. Ellebedy

Immunological imprinting: Understanding COVID-19

Cell, April 2023; doi.org/10.1016/j.immuni.2023.04.012

Abstract

Immunological imprinting generically refers to the effects prior exposures have on subsequent immune responses to, and eventually protection against, antigenically related viruses. Here, Koutsakos and Ellebedy explain different concepts and terms around imprinting and the fundamental immunological principles behind it. They also discuss the potential role imprinting may have in the context of COVID-19 vaccines.

Benjamin Charvet et al.

SARS-CoV-2 awakens ancient retroviral genes and the expression of proinflammatory HERV-W envelope protein in COVID-19 patients

Cell, April 2023; doi.org/10.1016/j.isci.2023.106604

Abstract

Patients with COVID-19 may develop abnormal inflammatory response, followed in some cases by severe disease and long-lasting syndromes. We show here that in vitro exposure to SARS-CoV-2 activates the expression of the human endogenous retrovirus (HERV) HERV-W proinflammatory envelope protein (ENV) in peripheral blood mononuclear cells from a subset of healthy donors, in ACE2 receptor and infection-independent manner. Plasma and/or sera of 221 COVID-19 patients from different cohorts, infected with successive SARS-CoV-2 variants including the Omicron, had detectable HERV-W ENV, which correlated with ENV expression in T-lymphocytes and peaked with the disease severity. HERV-W ENV was also found in post-mortem tissues of lungs, heart, gastrointestinal tract, brain olfactory bulb and nasal mucosa from COVID-19 patients. Altogether, these results demonstrate that SARS-CoV-2 could induce HERV-W envelope protein expression and suggest its involvement in the immunopathogenesis of certain COVID-19-associated syndromes and thereby its relevance in the development of personalized treatment of patients

Cosima T. Baldari et al.

Emerging roles of SARS-CoV-2 Spike-ACE2 in immune evasion and pathogenesis

Cell, April 2023; doi.org/10.1016/j.it.2023.04.001

Abstract

The COVID-19 pandemic, caused by the SARS-CoV-2 virus, has caused an estimated 5 billion infections and 20 million deaths by respiratory failure. In addition to the respiratory disease, SARS-CoV-2 infection has been associated with many extrapulmonary complications not easily explainable by the respiratory infection. A recent study showed that the SARS-CoV-2 spike protein, which mediates cell entry by binding to the ACE2 receptor, signals through ACE2 to change host cell behavior. In CD8+ T cells, Spike-dependent ACE2-mediated signaling suppresses immunological synapse formation and impairs their killing ability, leading to immune escape of virus-infected cells. In this opinion article, we discuss the consequences of ACE2 signaling on the immune response and propose that it contributes to the extrapulmonary manifestations of COVID-19.

QinyaXie et al.

Endogenous IFITMs boost SARS-coronavirus 1 and 2 replication whereas overexpression inhibits infection by relocalizing ACE2

Cell, March 2023; doi.org/10.1016/j.isci.2023.106395

Abstract

Opposing effects of interferon-induced transmembrane proteins (IFITMs 1, 2 and 3) on SARS-CoV-2 infection have been reported. The reasons for this are unclear and the role of IFITMs in infection of other human coronaviruses (hCoVs) remains poorly understood. Here, we demonstrate that endogenous expression of IFITM2 and/or IFITM3 is critical for efficient replication of SARS-CoV-1, SARS-CoV-2 and hCoV-OC43 but has little effect on MERS-, NL63-and 229E-hCoVs. In contrast, overexpression of IFITMs inhibits all these hCoVs, and the corresponding spike-containing pseudo-particles, except OC43, which is enhanced by IFITM3. We further demonstrate that overexpression of IFITMs impairs cell surface expression of ACE2 representing the entry receptor of SARS-CoVs and hCoV-NL63 but not hCoV-OC43. Our results explain the inhibitory effects of artificial IFITM overexpression on ACE2-tropic SARS-CoVs and show that three hCoVs, including major causative agents of severe respiratory disease, hijack IFITMs for efficient infection of human cells.

Lu Miao et al.

SIM imaging resolves endocytosis of SARS-CoV-2 spike RBD in living cells 

Cell, March 2023; doi.org/10.1016/j.chembiol.2023.02.001

https://www.cell.com/cell-chemical-biology/fulltext/S2451-9456(23)00032-6

Abstract

It is urgent to understand the infection mechanism of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) for the prevention and treatment of COVID-19. The infection of SARS-CoV-2 starts when the receptor-binding domain (RBD) of viral spike protein binds to angiotensin-converting enzyme 2 (ACE2) of the host cell, but the endocytosis details after this binding are not clear. Here, RBD and ACE2 were genetically coded and labeled with organic dyes to track RBD endocytosis in living cells. The photostable dyes enable long-term structured illumination microscopy (SIM) imaging and to quantify RBD-ACE2 binding (RAB) by the intensity ratio of RBD/ACE2 fluorescence. We resolved RAB endocytosis in living cells, including RBD-ACE2 recognition, cofactor-regulated membrane internalization, RAB-bearing vesicle formation and transport, RAB degradation, and downregulation of ACE2. The RAB was found to activate the RBD internalization. After vesicles were transported and matured within cells, RAB was finally degraded after being taken up by lysosomes. This strategy is a promising tool to understand the infection mechanism of SARS-CoV-2.

BiboZhu et al.

Inhibition of the mitochondrial pyruvate carrier simultaneously mitigates hyperinflammation and hyperglycemia in COVID-19

https://www.science.org/doi/10.1126/sciimmunol.adf0348

Abstract

The relationship between diabetes and COVID-19 is bi-directional: while individuals with diabetes and high blood glucose (hyperglycemia) are predisposed to severe COVID-19, SARS-CoV-2 infection can also cause hyperglycemia and exacerbate underlying metabolic syndrome. Therefore, interventions capable of breaking the network of SARS-CoV-2 infection, hyperglycemia, and hyper-inflammation, all factors that drive COVID-19 pathophysiology, are urgently needed. Here, we show that genetic ablation or pharmacological inhibition of mitochondrial pyruvate carrier (MPC) attenuates severe disease following influenza or SARS-CoV-2 pneumonia. MPC inhibition using a second-generation insulin sensitizer, MSDC-0602 K (MSDC), dampened pulmonary inflammation and promoted lung recovery, while concurrently reducing blood glucose levels and hyperlipidemia following viral pneumonia in obese mice. Mechanistically, MPC inhibition enhanced mitochondrial fitness and destabilized HIF-1α, leading to dampened virus-induced inflammatory responses in both murine and human lung macrophages. We further showed that MSDC enhanced responses to nirmatrelvir (the antiviral component of Paxlovid) to provide high levels of protection against severe host disease development following SARS-CoV-2 infection and suppressed cellular inflammation in human COVID-19 lung autopsies, demonstrating its translational potential for treating severe COVID-19. Collectively, we uncover a metabolic pathway that simultaneously modulates pulmonary inflammation, tissue recovery, and host metabolic health, presenting a synergistic therapeutic strategy to treat severe COVID-19, particularly in patients with underlying metabolic disease.

Varghese Edwin Hillary, Stanislaus Antony Ceasar

An update on COVID-19: SARS-CoV-2 variants, antiviral drugs, and vaccines

Cell; february 2023; doi.org/10.1016/j.heliyon.2023.e13952

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a highly contagious and pathogenic virus that first appeared in late December 2019. This SARS-CoV-2 causes an infection of an acute respiratory disease called “coronavirus infectious disease-2019 (COVID-19). The World Health Organization (WHO) declared this SARS-CoV-2 outbreak a great pandemic on March 11, 2020. As of January 31, 2023, SARS-CoV-2 recorded more than 67 million cases and over 6 million deaths. Recently, novel mutated variants of SARS-CoV are also creating a serious health concern worldwide, and the future novel variant is still mysterious. As infection cases of SARS-CoV-2 are increasing daily, scientists are trying to combat the disease using numerous antiviral drugs and vaccines against SARS-CoV-2. To our knowledge, this is the first comprehensive review that summarized the dynamic nature of SARS-CoV-2 transmission, SARS-CoV-2 variants (a variant of concern and variant of interest), antiviral drugs and vaccines utilized against SARS-CoV-2 at a glance. Hopefully, this review will enable the researcher to gain knowledge on SARS-CoV-2 variants and vaccines, which will also pave the way to identify efficient novel vaccines against forthcoming SARS-CoV-2 strains.

Loftus TJ, et al.

Overlapping but Disparate Inflammatory and Immunosuppressive Responses to SARS-CoV-2 and Bacterial Sepsis: An Immunological Time Course Analysis

Front Immunol.,

https://www.frontiersin.org/articles/10.3389/fimmu.2021.792448/full?utm_source=F-NTF&utm_medium=EMLX&utm_campaign=PRD_FEOPS_20170000_ARTICLE

CONTENUTO : In un contesto epidemiologico in cui parte della popolazione è immunizzata nei confronti di SARS-CoV2, ma le restrizioni sono più rilassate, il virus continua a circolare sotto la pressione evolutiva che los pinge verso un escape immunologico sempre maggiore. Questo studio, condotto in vitro, dimostra che l’interfaccia tra il « Receptor Binding Domain » e il suo recettore, ACE2, può sopportare un notevole numero di mutazioni conservado la sua funzione, consentendo però una sempre maggiore resitenza nei confronti dell’azione anticorpale.

COMMENTO : Intressante lavoro che profila gli eventi evolutivi che condizionano la sopravvivenza di SARS-CoV-2, attraverso mutazioni a livello del receptor binding domain (RBD), cioè la parte della proteina spike del virus che lega il recettore ACE2 presente sulle cellule dell’ospite e permette l’infezione. Tali mutazioni a livello di RBD sono favorevoli per la sopravvivenza evolutiva del virus se non interferiscono con il legame con ACE2 (e quindi con la capacità infettante virale), ma interferiscono soltanto con il legame degli anticorpi specifici, allo scopo di evitare il potere neutralizzante degli anticorpi (escape). Gli autori hanno identificato delle mutazioni a livello del RBD virale potenzialmente critiche per fare escape, in quanto esse, sotto la pressione immunologica, modificano la struttura di RBD, attraverso l'aggiunta di una catena glucidica a livello dell'atomo di azoto (N) di una catena laterale dell’aminoacidico asparagina (N-glicosilazione). Tale modifica biochimica avviene normalmente durante la sintesi proteica, affinchè la proteina glicosilata assuma la struttura tridimensionale corretta per la propra funzione. SARS-CoV-2 impiega questo meccanismo per generare nuove varianti che presentano diversi nuovi siti di N-glicosilazione. Ovviamente le varianti con maggior numero di cambiamenti dati dalla N-glicosilazione a livello di RBD sono più capaci di fare escape dagli anticorpi neutralizzanti in vitro, ma, attenzione, sono anche meno capaci di infettare perchè interferiscono con il legame con ACE2. D’altro canto questo bilanciamento sarebbe alla lunga favorevole per la selezione evolutiva virale in quanto permetterebbe che altre nuove mutazioni si possano selezionare sia per resistere ancora di più alla pressione immunologica, sia per ripristinare la capacità infettante del virus. La buona notizia è che comunque tali mutazioni indotte dalla N-glicosilazione, riducono solo parzialmente (soltanto di circa il 30%) la capacità neutralizzante degli anticorpi generati dopo vaccinazione (vaccini mRNA), soprattutto dopo ripetute somministrazioni del vaccino, il quale pertanto risulta molto efficace anche contro queste varianti. Teniamo sempre presente, inoltre, che tali varianti, anche quando capaci di fare escape dagli anticorpi e quindi di infettare, difficilmente potrebbero procurare malattie severe, e più difficilmente morte, nei vaccinati o guariti da una precedente infezione COVID-19, in quanto intervengo i famosi linfociti T che elimimano specificamente qualunque cellula infettata (serbatoio virale). A questo livello, i linfociti T « se ne fregano » della N-glicosilazione, in quanto vengono generati centinaia di linfociti T ognuno specifico per un pezzettino (peptide) del SARS-CoV-2, proprio per evitare che poche mutazioni possano interferire con la loro capacità di riconoscimento.

Tanya Ralli et al.

Decoding the bidirectional relationship between gut microbiota and COVID-19

Cell, March 2023; doi.org/10.1016/j.heliyon.2023.e13801

Abstract                                                                           

From late 2019, whole world has been facing COVID-19 pandemic which is caused by SARS-CoV-2 virus. This virus primarily attacks the respiratory tract and enter host cell by binding with angiotensin 2 converting enzyme receptors present on alveoli of the lungs. Despite its binding in the lungs, many patients have reported gastrointestinal symptoms and indeed, RNA of the virus have been found in faecal sample of patients. This observation gave a clue of the involvement of gut-lung axis in this disease development and progression. From several studies reported in past two years, intestinal microbiome has shown to have bidirectional link with lungs i.e., gut dysbiosis increases the tendency of infection with COVID-19 and coronavirus can also cause perturbations in intestinal microbial composition. Thus, in this review we have tried to figure out the mechanisms by which disturbances in the gut composition can increase the susceptibility to COVID-19. Understanding these mechanisms can play a crucial role in decreasing the disease outcomes by manipulating the gut microbiome using prebiotics, probiotics, or combination of two. Even, faecal microbiota transplantation can also show better results, but intensive clinical trials need to be done first.

Lipin Loo et al.

Fibroblast-expressed LRRC15 is a receptor for SARS-CoV-2 spike and controls antiviral and antifibrotic transcriptional programs

Journals Plos Org; February 2023; doi.org/10.1371/journal.pbio.3001967

Abstract

Although ACE2 is the primary receptor for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection, a systematic assessment of host factors that regulate binding to SARS-CoV-2 spike protein has not been described. Here, we use whole-genome CRISPR activation to identify host factors controlling cellular interactions with SARS-CoV-2. Our top hit was a TLR-related cell surface receptor called leucine-rich repeat-containing protein 15 (LRRC15). LRRC15 expression was sufficient to promote SARS-CoV-2 spike binding where they form a cell surface complex. LRRC15 mRNA is expressed in human collagen-producing lung myofibroblasts and LRRC15 protein is induced in severe Coronavirus Disease 2019 (COVID-19) infection where it can be found lining the airways. Mechanistically, LRRC15 does not itself support SARS-CoV-2 infection, but fibroblasts expressing LRRC15 can suppress both pseudotyped and authentic SARS-CoV-2 infection in trans. Moreover, LRRC15 expression in fibroblasts suppresses collagen production and promotes expression of IFIT, OAS, and MX-family antiviral factors. Overall, LRRC15 is a novel SARS-CoV-2 spike-binding receptor that can help control viral load and regulate antiviral and antifibrotic transcriptional programs in the context of COVID-19 infection.

Tada T. et al.

Prophylaxis and Treatment of SARS-CoV-2 infection by an ACE2 Receptor Decoy

Cell, January 2023; doi.org/10.1016/j.isci.2023.106092

Abstract

The emergence of SARS-CoV-2 variants with highly mutated spike proteins has presented an obstacle to the use of monoclonal antibodies for the prevention and treatment of SARS-CoV-2 infection. We show that a high affinity receptor decoy protein in which a modified ACE2 ectodomain is fused to a single domain of an immunoglobulin heavy chain Fc region dramatically suppressed virus loads in mice upon challenge with a high dose of parental SARS-CoV-2 or Omicron variants. The decoy also potently suppressed virus replication when administered shortly post-infection. The decoy approach offers protection against the current viral variants and, potentially, against SARS-CoV-2 variants that may emerge with the continued evolution of the spike protein or novel viruses that use ACE2 for virus entry.

Jasper Fuk-Woo Chan et al.

Altered host protease determinants for SARS-CoV-2 Omicron

Science, January 2023; doi/10.1126/sciadv.add3867

Abstract

Successful severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection requires proteolytic cleavage of the viral spike protein. While the role of the host transmembrane protease serine 2 in SARS-CoV-2 infection is widely recognized, the involvement of other proteases capable of facilitating SARS-CoV-2 entry remains incompletely explored. Here, we show that multiple members from the membrane-type matrix metalloproteinase (MT-MMP) and a disintegrin and metalloproteinase families can mediate SARS-CoV-2 entry. Inhibition of MT-MMPs significantly reduces SARS-CoV-2 replication in vitro and in vivo. Mechanistically, we show that MT-MMPs can cleave SARS-CoV-2 spike and angiotensin-converting enzyme 2 and facilitate spike-mediated fusion. We further demonstrate that Omicron BA.1 has an increased efficiency on MT-MMP usage, while an altered efficiency on transmembrane serine protease usage for virus entry compared with that of ancestral SARS-CoV-2. These results reveal additional protease determinants for SARS-CoV-2 infection and enhance our understanding on the biology of coronavirus entry.

Wigerblad G.et al.

Spleen tyrosine kinase inhibition restores myeloid homeostasis in COVID-19

Science, Januari 2023; doi/10.1126/sciadv.ade8272

Abstract

Spleen tyrosine kinase (SYK) is a previously unidentified therapeutic target that inhibits neutrophil and macrophage activation in coronavirus disease 2019 (COVID-19). Fostamatinib, a SYK inhibitor, was studied in a phase 2 placebo-controlled randomized clinical trial and was associated with improvements in many secondary end points related to efficacy. Here, we used a multiomic approach to evaluate cellular and soluble immune mediator responses of patients enrolled in this trial. We demonstrated that SYK inhibition was associated with reduced neutrophil activation, increased circulation of mature neutrophils (CD10+CD33−), and decreased circulation of low-density granulocytes and polymorphonuclear myeloid-derived suppressor cells (HLA-DR−CD33+CD11b−). SYK inhibition was also associated with normalization of transcriptional activity in circulating monocytes relative to healthy controls, an increase in frequency of circulating nonclassical and HLA-DRhi classical monocyte populations, and restoration of interferon responses. Together, these data suggest that SYK inhibition may mitigate proinflammatory myeloid cellular and soluble mediator responses thought to contribute to immunopathogenesis of severe COVID-19.

Chenxu Guo et al.

The D614G mutation redirects SARS-CoV-2 spike to lysosomes and suppresses deleterious traits of the furin cleavage site insertion mutation

Science, December 2022; doi/10.1126/sciadv.ade5085

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) egress occurs by lysosomal exocytosis. We show that the Spike D614G mutation enhances Spike trafficking to lysosomes, drives Spike-mediated reprogramming of lysosomes, and reduces cell surface Spike expression by ~3-fold. D614G is not a human-specific adaptation. Rather, it is an adaptation to the earlier furin cleavage site insertion (FCSI) mutation that occurred at the genesis of SARS-CoV-2. While advantageous to the virus, furin cleavage of spike has deleterious effects on spike structure and function, inhibiting its trafficking to lysosomes and impairing its infectivity by the transmembrane serine protease 2(TMPRSS2)-independent, endolysosomal pathway. D614G restores spike trafficking to lysosomes and enhances the earliest events in SARS-CoV-2 infectivity, while spike mutations that restore SARS-CoV-2’s TMPRSS2-independent infectivity restore spike’s trafficking to lysosomes. Together, these and other results show that D614G is an intragenic suppressor of deleterious traits linked to the FCSI and lend additional support to the endolysosomal model of SARS-CoV-2 egress and entry.

Lili Li et al.

Identification of an immunogenic epitope and protective antibody against the furin cleavage site of SARS-CoV-2 Lili Li et al

Lancet, December 2022; doi.org/10.1016/j.ebiom.2022.104401

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of the global coronavirus disease 2019 (COVID-19) pandemic, contains a unique, four amino acid (aa) “PRRA” insertion in the spike (S) protein that creates a transmembrane protease serine 2 (TMPRSS2)/furin cleavage site and enhances viral infectivity. More research into immunogenic epitopes and protective antibodies against this SARS-CoV-2 furin cleavage site is needed. Methods Combining computational and experimental methods, we identified and characterized an immunogenic epitope overlapping the furin cleavage site that detects antibodies in COVID-19 patients and elicits strong antibody responses in immunized mice. We also identified a high-affinity monoclonal antibody from COVID-19 patient peripheral blood mononuclear cells; the antibody directly binds the furin cleavage site and protects against SARS-CoV-2 infection in a mouse model. Findings The presence of “PRRA” amino acids in the S protein of SARS-CoV-2 not only creates a furin cleavage site but also generates an immunogenic epitope that elicits an antibody response in COVID-19 patients. An antibody against this epitope protected against SARS-CoV-2 infection in mice. Interpretation The immunogenic epitope and protective antibody we have identified may augment our strategy in handling COVID-19 epidemic.

Barnett K.C. et al.

An epithelial-immune circuit amplifies inflammasome and IL-6 responses to SARS-CoV-2

CellPress, December 2022; doi.org/10.1016/j.chom.2022.12.005

Abstract

Elevated levels of the cytokines IL-1β and IL-6 are associated with severe COVID-19. Investigating the underlying mechanisms, we find that while primary human airway epithelia (HAE) have functional inflammasomes and support SARS-CoV-2 replication, they are not the source of IL-1β released upon infection. In leukocytes, the SARS-CoV-2 E protein upregulates inflammasome gene transcription via TLR2 to prime, but not activate, inflammasomes. SARSCoV-2-infected HAE supply a second signal, which includes genomic and mitochondrial DNA, to stimulate leukocyte IL-1β release. Nuclease treatment, STING and caspase-1 inhibition but not NLRP3 inhibition blocked leukocyte IL-1β release. After release, IL-1β stimulates IL-6 secretion from HAE. Therefore, infection alone does not increase IL-1β secretion by either cell type. Rather, bi-directional interactions between the SARS-CoV-2-infected epithelium and immune bystanders stimulates both IL-1β and IL-6, creating a pro-inflammatory cytokine circuit. Consistent with these observations, patient autopsy lungs show elevated myeloid inflammasome gene signatures in severe COVID-19.

Tojo K et al.

Early alveolar epithelial cell necrosis is a potential driver of COVID-19-induced acute respiratory distress syndrome

Cell, December 2022; doi.org/10.1016/j.isci.2022.105748

Abstract

Acute respiratory distress syndrome (ARDS) with COVID-19 is aggravated by hyperinflammatory responses even after the peak of viral load has passed; however, its underlying mechanisms remain unclear. In the present study, analysis of the alveolar tissue injury markers and epithelial cell death markers in patients with COVID-19 revealed that COVID-19-induced ARDS was characterized by alveolar epithelial necrosis at an early disease stage. Collectively, necrosis, including necroptosis and pyroptosis, is the predominant form of alveolar epithelial cell death at an early disease stage and subsequent release of DAMPs is a potential driver of COVID-19- induced ARDS.

M.J et al.

SARS-CoV-2 escapes direct NK cell killing through Nsp1-mediated downregulation of ligands for NKG2D Lee

Cell, December 2022; doi.org/10.1016/j.celrep.2022.111892

Abstract

Natural killer (NK) cells are cytotoxic effector cells that target and lyse virally-infected cells; many viruses therefore encode mechanisms to escape such NK cell killing. Here, we interrogate the ability of SARS-CoV-2 to modulate NK cell recognition and lysis of infected cells. The authors find that NK cells exhibit poor cytotoxic responses against SARS-CoV-2-infected targets, preferentially killing uninfected bystander cells.

Collectively, our work demonstrates that SARS-CoV-2 evades direct NK cell cytotoxicity and describes a mechanism by which this occurs.

Chien-Ting Wu et al.

SARS-CoV-2 replication in airway epithelia requires motile cilia and microvillar reprogramming

CELL, December 2022; doi.org/10.1016/j.cell.2022.11.030

Abstract

How SARS-CoV-2 penetrates the airway barrier of mucus and periciliary mucins to infect nasal epithelium remains unclear. Using primary nasal epithelial organoid cultures, we found the virus attaches to motile cilia via the ACE2 receptor. SARS-CoV-2 traverses the mucus layer, using motile cilia as tracks to access the cell body. Depleting cilia blocks infection for SARS-CoV-2 and other respiratory viruses. SARS-CoV-2 progeny attach to airway microvilli 24 hours post-infection and trigger formation of apically extended and highly branched microvilli that organize viral egress from the microvilli back into the mucus layer, supporting a model of virus dispersion throughout airway tissue via mucociliary transport. Phosphoproteomics and kinase inhibition reveal microvillar remodeling is regulated by PAK kinases. Importantly, Omicron variants bind with higher affinity to motile cilia and show accelerated viral entry. Our work suggests that motile cilia, microvilli, and mucociliary-dependent mucus flow are critical for efficient virus replication in nasal epithelia.

Ropa J. et al.

Human Hematopoietic Stem, Progenitor, and Immune Cells Respond Ex Vivo to SARS-CoV-2 Spike Protein

Springer, October 2020; doi.org/10.1007/s12015-020-10056-z

Abstract

Despite evidence that SARS-CoV-2 infection is systemic in nature, there is little known about the  effects that SARS-CoV-2 infection or exposure has on many host cell types, including primitive and  mature hematopoietic cells. The hematopoietic system is responsible for giving rise to the very  immune cells that defend against viral infection and is a source of hematopoietic stem cells (HSCs) and progenitor cells (HPCs) which are used for hematopoietic cell transplantation (HCT) to treat

hematologic disorders, thus there is a strong need to understand how exposure to the virus may affect hematopoietic cell functions. We examined the expression of ACE2, to which SARS-CoV-2 Spike (S) protein binds to facilitate viral entry, in cord blood derived HSCs/HPCs and in peripheral blood derived immune cell subtypes. That these effects are  induced by recombinant S protein alone and not the infectious viral particle suggests that simple exposure to SARS-CoV-2 may impact HSCs/HPCs and immune cells via S protein interactions with the cells, regardless of whether they can be infected. These data have implications for immune response to SARS-CoV-2 and for HCT.

Smith N et al

Defective activation and regulation of type I interferon immunity is associated with increasing COVID-19 severity

Nature, November 2022; doi.org/10.1038/s41467-022-34895-1

Abstract

Host immunity to infection with SARS-CoV-2 is highly variable, dictating diverse clinical outcomes

ranging from asymptomatic to severe disease and death. We previously reported reduced type I interferon in severe COVID-19 patients preceded clinical worsening. Further studies identified genetic mutations in loci of the TLR3- or TLR7-dependent interferon-I pathways, or neutralizing interferon-I autoantibodies as risk factors for development of COVID-19 pneumonia. Here we show in patient cohorts with different severities of COVID-19, that baseline plasma interferon α measures differ according to the immunoassay used, timing of sampling, the interferon α subtype measured, and the presence of autoantibodies. These results may explain the dichotomy of the poor clinical response to interferon-I based treatments in late stage COVID-19, despite the importance of interferon-I in early acute infection and may guide alternative therapeutic strategies.

Nelde A. et al

Increased soluble HLA in COVID-19 present a disease-related, diverse immunopeptidome associated with T cell immunity

Cell, November 2022; doi.org/10.1016/j.isci.2022.105643

Abstract

HLA-presented antigenic peptides are central components of T cell-based immunity in infectious disease. Beside HLA molecules on cell surfaces, soluble HLA molecules (sHLA) are released in the blood suggested to impact cellular immune responses. We demonstrated that sHLA levels were significantly increased in COVID-19 patients and convalescent individuals compared to a control cohort and positively correlated with SARS-CoV-2-directed cellular immunity. Of note, patients with severe courses of COVID-19 showed reduced sHLA levels.

Why hybrid immunity is so triggering

The Lancet, November 2022, doi.org/10.1016/S1473-3099(22)00746-0

Abstract

It is becoming clear that hybrid immunity, that is immunity provided by a combination of infection and vaccination, provides better protection against subsequent COVID-19 than either vaccination or infection alone – higher antibody levels, less frequent and less severe infection. However, the picture is complex due to a chequered pattern of immunity in the population. People differ not only in their history of infection timing and infecting variant, but also in the type of vaccine they received, how many doses and finally, how well their immune system responded.

So, where do we go from here? Chequered immunity patterns in the population, waning of immune responses and the rise of immune-evasive variants such as BQ.1.1 or XBB, which might threaten protection afforded by hybrid immunity, require a multi-layered approached. First, we need an agile, scalable and fast infrastructure to develop and approve new vaccines that either target newly emerging variants, are pan-variant, and/or provide mucosal protection. However, we do not have the same will and funding as earlier during the pandemic for new vaccines, nor to track the variant landscape. While these are urgent needs, we should not forget non-pharmaceutical interventions, which can be adapted to the current local risk level. Although these interventions can have societal and economic consequences, a wildfire of COVID-19 will cost us too, causing disruption, disability, and death. If one must make any political arguments with hybrid immunity, it should be that people who had no access to vaccines yet must urgently get them.

Brest P et al

Host genetic variability and determinants of severe COVID-19

CELL, November 2022; doi.org/10.1016/j.tig.2022.10.003

Abstract

Since the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outbreak, convergent studies have provided evidence that host genetic background may contribute to the development of severe coronavirus disease (COVID-19). Here, we summarize how some genetic variations, such as in SARS-CoV-2 receptor angiotensin-converting enzyme 2 or interferon signaling pathway, may help to understand why some individuals can develop severe COVID-19 persistence has decreased.

Isobe A. et al.

ACE2 N-glycosylation modulates interactions with SARS-CoV-2 spike protein in a site-specific manner

Nature, November 2022; doi.org/10.1038/s42003-022-04170-6

Abstract

SARS-CoV-2 has evolved continuously and accumulated spike mutations with each variant having a different binding for the cellular ACE2 receptor. It is not known whether the interactions between such mutated spikes and ACE2 glycans are conserved among different variant lineages. Here, we focused on three ACE2 glycosylation sites (53, 90 and 322) that are geometrically close to spike binding sites and investigated the effect of their glycosylation pattern on spike affinity. Our study provides insights for a better understanding of the importance of ACE2 glycosylation on ACE2/SARS-CoV-2 spike interaction and guidance for further optimization of soluble ACE2 for therapeutic use.

Fang Y et al.

An antibody that neutralizes SARS-CoV-1 and SARS-CoV-2 by binding to a conserved spike epitope outside the receptor binding motif

Science Immunology, August; doi/10.1126/sciimmunol.abp9962

Abstract

The authors used the LIBRA-seq technology, which identified SARS-CoV-2–specific B cells via DNA barcoding and subsequently single-cell sequenced BCRs, to identify an antibody, SW186, which could neutralize major SARS-CoV-2 variants of concern, including Beta, Delta, and Omicron, as well as SARS-CoV-1.

Arrindell J. et al.

Vimentin is an important ACE2 co-receptor for SARS-CoV-2 in epithelial cells

iScience, October 2022; doi.org/10.1016/j.isci.2022.105463

Abstract

The authors showed that upon infection, vimentin was upregulated at the cell surface, where it interacts with ACE2 for SARS-CoV-2 entry. They demonstrated a direct interaction between SARS-CoV-2 spike protein, ACE2 and vimentin in epithelial cells.

Sauerwald N. et al.

Pre-infection antiviral innate immunity contributes to sex differences in SARS-CoV-2 infection

CELL Systems, October 2022; doi.org/10.1016/j.cels.2022.10.005

Abstract

Male sex is a major risk factor for SARS-CoV-2 infection severity. To understand the basis for this sex difference, the authors studied SARS-CoV-2 infection in a young adult cohort of United States Marine recruits.

P. Sun et al.

Asymptomatic or symptomatic SARS-CoV-2 infection plus vaccination confers increased adaptive immunity to Variants of Concern.

iScience, October 2022;doi.org/10.1016/j.isci.2022.105202

Abstract

The evolution of SARS-CoV-2 requires monitoring the capability of immune responses to cross-recognizeVariants of Concern (VOC). In this study the authorsexaminedserological and cell-mediated immune memory to SARS-CoV-2 variants, including Omicron, among a cohort of 18-21-year-old Marines with a history of eitherasymptomatic or mild SARS-CoV-2 infection 6 to 14 monthsearlier.

H. Cohen-Dvashi et al.

Anti-SARS-CoV-2 immunoadhesin remains effective against Omicron and other emerging variants of concern

iScience, October2022;doi: 10.1016/j.isci.2022.105193

Abstract

The authors evaluate an ACE2-based immunoadhesin that was developed early in the pandemic against some of the recent variants of concern (VoCs), including the Delta and the Omicron variants. 

A. Aviv

The bullwhipeffect, T-celltelomeres, and SARS-CoV-2

Lancet HealthyLongevity, October 2022; doi.org/10.1016/S2666-7568(22)00190-8

Abstract

Bothmyeloidcells, whichcontribute to innate immunity, and lymphoidcells, which dominate adaptiveimmunity, partake in defendingagainst SARS-CoV-2. In response to the virus, the otherwise slow haematopoietic production supply chain quicklyunleashesitspreconfiguredmyeloidelement, whichlargelyresists a bullwhip-like effect. By contrast, the lymphoidelement risks a bullwhip-like effectwhenitproduces T cells and B cellsthat are specificallydesigned to clear the virus. As T-cell production istelomere-lengthdependent and telomeresshorten with age, olderadults are athigher risk of a T-cellshortfallwhencontracting SARS-CoV-2 than are youngeradults. A poorlycalibratedadaptive immune response, stemming from a bullwhip-like effect, compounded by a T-cell deficit, mightthuscontribute to the propensity of people with inherently short T-celltelomeres to develop severe COVID-19. The immune systems of theseindividualsmightalso generate an inadequate T-cellresponse to anti-SARS-CoV-2 vaccination.

J. Ankerhold et al.

Circulating multimeric immune complexes contribute to immunopathology in COVID-19

Nature Communications, September 2022; doi.org/10.1038/s41467-022-32867-z

Abstract

A dysregulated immune response with high levels of SARS-CoV-2 specific IgG antibodies characterizes patients with severe or critical COVID-19. Although a robust IgG response is considered to be protective, excessive triggering of activating Fc-gamma-receptors (FcγRs) could be detrimental and cause immunopathology. The study documents excessive FcγRIIIA/CD16A activation in patients developing severe or critical COVID-19 but not in those with mild disease.

S. DeWolf et al.

SARS-CoV-2 in immunocompromised individuals

Immunity, September 2022; doi: doi.org/10.1016/j.immuni.2022.09.006

Abstract

Immunocompromised individuals and particularly those with hematologic malignancies are at increased risk for SARS-CoV-2-associated morbidity and mortality due to immunologic deficits that limit prevention, treatment, and clearance of the virus. Understanding the natural history of viral infections in people with impaired immunity due to underlying conditions, immunosuppressive therapy, or a combination thereof has emerged as a critical area of investigation during the COVID-19 pandemic. Studies focused on these individuals have provided key insights into aspects of innate and adaptive immunity underlying both the anti-viral immune response and excess inflammation in the setting of COVID-19. This review presents what is known about distinct states of immunologic vulnerability to SARS-CoV-2 and how this information can be harnessed to improve prevention and treatment strategies for immunologically high-risk populations.

Y. Gao et al.

Immunodeficiency syndromes differentially impact the functional profile of SARS-CoV-2-specific T cells elicited by mRNA vaccination

Immunity, September 2022; doi: 10.1016/j.immuni.2022.07.005

Abstract

Many immunocompromised patients mount suboptimal humoral immunity after SARS-CoV-2 mRNA vaccination. The authors assessed the single-cell profile of SARS-CoV-2-specific T cells post-mRNA vaccination in healthy individuals and patients with various forms of immunodeficiencies. Impaired vaccine-induced cell-mediated immunity was observed in many immunocompromised patients, particularly in solid-organ transplant and chronic lymphocytic leukemia patients. The data provide the functional continuum of SARS-CoV-2-specific T cell responses post-mRNA vaccination, highlighting that cell-mediated immunity is of variable functional quality across immunodeficiency syndromes.

CDC, April 2022;

SARS-CoV-2 VariantClassifications and Definitions

https://www.cdc.gov/coronavirus/2019-ncov/variants/variant-classifications.html?CDC_AA_refVal=https%3A%2F%2Fwww.cdc.gov%2Fcoronavirus%2F2019-ncov%2Fvariants%2Fvariant-info.html

Abstract

Viruses like SARS-CoV-2 continuously evolve as changes in the genetic code (caused by genetic mutations or viral recombination) occur during replication of the genome.

C.B. Jackson et al.

Mechanisms of SARS-CoV-2 entry into cells

Nature Reviews Molecular Cell Biology, October 2021; doi.org/10.1038/s41580-021-00418-x

Abstract

The unprecedented public health and economic impact of the COVID-19 pandemic caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been met with an equally unprecedented scientific response. Much of this response has focused, appropriately, on the mechanisms of SARS-CoV-2 entry into host cells, and in particular the binding of the spike (S) protein to its receptor, angiotensin-converting enzyme 2 (ACE2), and subsequent membrane fusion. This Review provides the structural and cellular foundations for understanding the multistep SARS-CoV-2 entry process, including S protein synthesis, S protein structure, conformational transitions necessary for association of the S protein with ACE2, engagement of the receptor-binding domain of the S protein with ACE2, proteolytic activation of the S protein, endocytosis and membrane fusion.

S. Fosatiet al.

Antioxidants and clinical outcomes of patients with coronavirus disease 2019: A systematic review of observational and interventional studies

Food Science and Nutrition, September 2022; doi.org/10.1002/fsn3.3034

Abstract

Coronavirus disease 2019 (COVID-19) is a newly emerging viral infection caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Oxidative stress appears to be a prominent contributor to the pathogenicity of SARS-CoV-2. Therefore, the authors carried out a systematic review of human observational and interventional studies to investigate the role of some antioxidants such as vitamins A, E, D, and C, selenium, zinc, and α-lipoic acid in the main clinical outcomes of subjects with COVID-19. The results showed the promising role of vitamin C in inflammation, Horowitz index, and mortality; vitamin D in disease manifestations and severity, inflammatory markers, lung involvement, ventilation requirement, hospitalization, intensive care unit (ICU) admission, and mortality; selenium in cure rate and mortality; and zinc in ventilation requirement, hospitalization, ICU admission, biomarkers of inflammation and bacterial infection, and disease complications. In conclusion, it seems that antioxidants, especially vitamins C and D, selenium, and zinc, can improve multiple COVID-19 clinical outcomes. Nevertheless, more studies are necessary to affirm these results.

M.C. Woodruff et al.

Dysregulated naïve B cells and de novo autoreactivity in severe COVID-19

Nature, August 2022; doi: 10.1038/s41586-022-05273-0

Abstract

Severe SARS-CoV-2 infection has been associated with highly inflammatory immune activation since the earliest days of the COVID-19 pandemic. More recently, these responses have been associated with the emergence of self-reactive antibodies with pathologic potential, although their origins and resolution have remained unclear. Previously, scientists have identified extrafollicular B cell activation, a pathway associated with the formation of new autoreactive antibodies in chronic autoimmunity, as a dominant feature of severe/critical COVID-19. Here, using single-cell B cell repertoire analysis of patients with mild and severe disease, the authors identify the expansion of a naïve-derived, low-mutation IgG1 population of antibody secreting cells (ASCs) reflecting features of low selective pressure. Further they identify the contraction of this pathway upon recovery, re-establishment of tolerance standards, and concomitant loss of acute-derived ASCs irrespective of antigen specificity. In total, this study reveals the origins, breadth, and resolution of autoreactivity in severe COVID-19, with implications for early intervention and treatment of patients with post-COVID sequelae.

A. Bertoletti et al.

SARS-CoV-2-specific T cells in the changing landscape of the COVID-19 pandemic

Immunity, August 2022; doi: 10.1016/j.immuni.2022.08.008

Abstract

Since the onset of the coronavirus disease 2019 (COVID-19) pandemic, multiple severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants with increasing ability to evade neutralizing antibodies have emerged. Thus, earlier interest in defining the correlates of protection from infection, mainly mediated by humoral immunity, has shifted to correlates of protection from disease, which require a more comprehensive analysis of both humoral and cellular immunity. In this review, we summarized the evidence that supports the role of SARS-CoV-2-specific T cells induced by infection, by vaccination or by their combination (defined as hybrid immunity) in disease protection. We then analyzed the different epidemiological and virological variables that can modify the magnitude, function, and anatomical localization of SARS-CoV-2-specific T cells and their influence in the possible ability of T cells to protect the host from severe COVID-19 development.

Y.C. Bartsch et al.

SARS-CoV-2 mRNA vaccination elicits robust antibody responses in children

Sci Transl Med, July 2022; doi: 10.1126/scitranslmed.abn9237

Abstract

Although children have been largely spared from coronavirus disease 2019 (COVID-19), the emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOC) with increased transmissibility, combined with fluctuating mask mandates and school re-openings, have led to increased infections and disease among children. Thus, there is an urgent need to roll out COVID-19 vaccines to children of all ages. However, whether children respond equivalently to adults to mRNA vaccines and whether dosing will elicit optimal immunity remains unclear. Here we aimed to deeply profile the vaccine-induced humoral immune response in 6 to 11 year old children receiving either a pediatric (50 μg) or adult (100 μg) dose of the mRNA-1273 vaccine and to compare these responses to vaccinated adults, infected children, and children that experienced multisystem inflammatory syndrome in children (MIS-C). Children elicited an IgG-dominant vaccine-induced immune response, surpassing adults at a matched 100 μg dose, but more variable immunity at a 50 μg dose. Irrespective of titer, children generated antibodies with enhanced Fc-receptor binding capacity. Moreover, like adults, children generated cross-VOC humoral immunity, marked by a decline of omicron-specific receptor binding domain-binding, but robustly preserved omicron spike protein-binding. Fc-receptor binding capabilities were also preserved in a dose dependent manner. These data indicate that both the 50 μg and 100 μg doses of mRNA vaccination in children elicits robust cross-VOC antibody responses and that 100 μg doses in children results in highly preserved omicron-specific functional humoral immunity.

M. Mello et al.

Public Health Law after Covid-19

N Engl J Med, September 2021; doi: 10.1056/NEJMp2112193

Abstract

Covid-19 has spurred an outbreak of a different kind: litigation. To combat the pandemic, officials imposed extensive community-level mitigation measures using their broad but largely untested emergency powers. In response, more than 1000 suits challenged orders shuttering businesses, banning indoor worship services, restricting travel, and mandating mask wearing.¹ As with other social aspects of the pandemic, this litigation will have lasting effects.

K. Guo et al.

Interferon Resistance of Emerging SARS-CoV-2 Variants

bioRxiv, December 2021; doi: 10.1101/2021.03.20.436257

Abstract

The emergence of SARS-CoV-2 variants with enhanced transmissibility, pathogenesis and resistance to vaccines presents urgent challenges for curbing the COVID-19 pandemic. While Spike mutations that enhance virus infectivity or neutralizing antibody evasion may drive the emergence of these novel variants, studies documenting a critical role for interferon responses in the early control of SARS-CoV-2 infection, combined with the presence of viral genes that limit these responses, suggest that interferons may also influence SARS-CoV-2 evolution. Here, we compared the potency of 17 different human interferons against multiple viral lineages sampled during the course of the global outbreak, including ancestral and four major variants of concern. Our data reveal increased interferon resistance in emerging SARS-CoV-2 variants, suggesting that evasion of innate immunity may be a significant, ongoing driving force for SARS-CoV-2 evolution. These findings have implications for the increased lethality of emerging variants and highlight the interferon subtypes that may be most successful in the treatment of early infections.

J.E. Pekar et al.

The molecular epidemiology of multiple zoonotic origins of SARS-CoV-2

Science, July 2022 ; doi: 10.1126/science.abp8337

Abstract

Understanding the circumstances that lead to pandemics is important for their prevention. Here, we analyze the genomic diversity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) early in the coronavirus disease 2019 (COVID-19) pandemic. We show that SARS-CoV-2 genomic diversity before February 2020 likely comprised only two distinct viral lineages, denoted A and B. Phylodynamic rooting methods, coupled with epidemic simulations, reveal that these lineages were the result of at least two separate cross-species transmission events into humans. The first zoonotic transmission likely involved lineage B viruses around 18 November 2019 (23 October-8 December), while the separate introduction of lineage A likely occurred within weeks of this event. These findings indicate that it is unlikely that SARS-CoV-2 circulated widely in humans prior to November 2019 and define the narrow window between when SARS-CoV-2 first jumped into humans and when the first cases of COVID-19 were reported. As with other coronaviruses, SARS-CoV-2 emergence likely resulted from multiple zoonotic events.

M. Worobey et al.

The Huanan Seafood Wholesale Market in Wuhan was the early epicenter of the COVID-19 pandemic

Science, July 2022; doi: 10.1126/science.abp8715

Abstract

Understanding how severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in 2019 is critical to preventing zoonotic outbreaks before they become the next pandemic. The Huanan Seafood Wholesale Market in Wuhan, China, was identified as a likely source of cases in early reports but later this conclusion became controversial. We show the earliest known COVID-19 cases from December 2019, including those without reported direct links, were geographically centered on this market. We report that live SARS-CoV-2 susceptible mammals were sold at the market in late 2019 and, within the market, SARS-CoV-2-positive environmental samples were spatially associated with vendors selling live mammals. While there is insufficient evidence to define upstream events, and exact circumstances remain obscure, our analyses indicate that the emergence of SARS-CoV-2 occurred via the live wildlife trade in China, and show that the Huanan market was the epicenter of the COVID-19 pandemic.

E.S. Huseby et al.

The perception and response of T cells to a changing environment are based on the law of initial value

Science, May 2022; doi: 10.1126/scisignal.abj9842

Abstract

αβ T cells are critical components of the adaptive immune system and are capable of inducing sterilizing immunity after pathogen infection and eliminating transformed tumor cells. The development and function of T cells are controlled through the T cell antigen receptor, which recognizes peptides displayed on major histocompatibility complex (MHC) molecules. Here, we review how T cells generate the ability to recognize self-peptide-bound MHC molecules and use signals derived from these interactions to instruct cellular development, activation thresholds, and functional specialization in the steady state and during immune responses. We argue that the basic tenants of T cell development and function follow Weber-Fetcher's law of just noticeable differences and Wilder's law of initial value. Together, these laws argue that the ability of a system to respond and the quality of that response are scalable to the basal state of that system. Manifestation of these laws in T cells generates clone-specific activation thresholds that are based on perceivable differences between homeostasis and pathogen encounter (self versus nonself discrimination), as well as poised states for subsequent differentiation into specific effector cell lineages.

W. Zhang et al.

SARS-CoV-2 infection results in immune responses in the respiratory tract and peripheral blood that suggest mechanisms of disease severity

Nature Communications, May 2022; doi.org/10.1038/s41467-022-30088-y

Abstract

Respiratory tract infection with SARS-CoV-2 results in varying immunopathology underlying COVID-19. We examine cellular, humoral and cytokine responses covering 382 immune components in longitudinal blood and respiratory samples from hospitalized COVID-19 patients. SARS-CoV-2-specific IgM, IgG, IgA are detected in respiratory tract and blood, however, receptor-binding domain (RBD)-specific IgM and IgG seroconversion is enhanced in respiratory specimens. SARS-CoV-2 neutralization activity in respiratory samples correlates with RBD-specific IgM and IgG levels. Cytokines/chemokines vary between respiratory samples and plasma, indicating that inflammation should be assessed in respiratory specimens to understand immunopathology. IFN-α2 and IL-12p70 in endotracheal aspirate and neutralization in sputum negatively correlate with duration of hospital stay. Diverse immune subsets are detected in respiratory samples, dominated by neutrophils. Importantly, dexamethasone treatment does not affect humoral responses in blood of COVID-19 patients. Our study unveils differential immune responses between respiratory samples and blood, and shows how drug therapy affects immune responses during COVID-19.

C. Gaebler et al.

Evolution of antibody immunity to SARS-CoV-2

Nature, January 2021; doi.org/10.1038/s41586-021-03207-w

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected 78 million individuals and is responsible for over 1.7 million deaths to date. Infection is associated with the development of variable levels of antibodies with neutralizing activity, which can protect against infection in animal models1^,2. Antibody levels decrease with time, but, to our knowledge, the nature and quality of the memory B cells that would be required to produce antibodies upon reinfection has not been examined. Here we report on the humoral memory response in a cohort of 87 individuals assessed at 1.3 and 6.2 months after infection with SARS-CoV-2. We find that titres of IgM and IgG antibodies against the receptor-binding domain (RBD) of the spike protein of SARS-CoV-2 decrease significantly over this time period, with IgA being less affected. Concurrently, neutralizing activity in plasma decreases by fivefold in pseudotype virus assays. By contrast, the number of RBD-specific memory B cells remains unchanged at 6.2 months after infection. Memory B cells display clonal turnover after 6.2 months, and the antibodies that they express have greater somatic hypermutation, resistance to RBD mutations and increased potency, indicative of continued evolution of the humoral response. Immunofluorescence and PCR analyses of intestinal biopsies obtained from asymptomatic individuals at 4 months after the onset of coronavirus disease 2019 (COVID-19) revealed the persistence of SARS-CoV-2 nucleic acids and immunoreactivity in the small bowel of 7 out of 14 individuals. We conclude that the memory B cell response to SARS-CoV-2 evolves between 1.3 and 6.2 months after infection in a manner that is consistent with antigen persistence.

M. Petillo et al.

Increase of SARS-CoV-2 RNA load in faecal samples prompts for rethinking of SARS-CoV-2 biology and COVID-19 epidemiology.

JRC Publications Repository, 2021; doi.org/10.12688/f1000research.52540.3

Abstract

Scientific evidence for the involvement of human microbiota in the development of COVID-19 disease was reported recently. We elaborated these findings further and collected data on the relationship between faecal bacteria, isolated from stool from COVID-19 patients, and SARS-CoV-2. The preliminary results suggest that SARS-CoV-2 replicates in bacterial growth medium inoculated with a stool sample from an infected patient and that the replication follows bacterial growth.These results are unexpected and when confirmed on large sample sizes hint towards novel hypotheses on the biology of SARS-CoV-2 and on the COVID-19 epidemiology. The data reported here suggest a possible ‘bacteriophage-like’ behaviour of SARS-CoV-2, which to our knowledge was never observed or described before. The discovery of possible new modes of action of SARS-CoV-2 has far-reaching implications for the prevention and the treatment of the disease, necessitating quick sharing of even preliminary findings with the global scientific community.

C. Brogna et al.

Could SARS-CoV-2 Have Bacteriophage Behavior or Induce the Activity of Other Bacteriophages?

Vaccines, April 2022; doi.org/10.3390/vaccines10050708

Abstract

SARS-CoV-2 has become one of the most studied viruses of the last century. It was assumed that the only possible host for these types of viruses was mammalian eukaryotic cells. Our recent studies show that microorganisms in the human gastrointestinal tract affect the severity of COVID-19 and for the first time provide indications that the virus might replicate in gut bacteria. In order to further support these findings, in the present work, cultures of bacteria from the human microbiome and SARS-CoV-2 were analyzed by electron and fluorescence microscopy. The images presented in this article, in association with the nitrogen (¹⁵N) isotope-labeled culture medium experiment, suggest that SARS-CoV-2 could also infect bacteria in the gut microbiota, indicating that SARS-CoV-2 could act as a bacteriophage. Our results add new knowledge to the understanding of the mechanisms of SARS-CoV-2 infection and fill gaps in the study of the interactions between SARS-CoV-2 and non-mammalian cells. These findings could be useful in suggesting specific new pharmacological solutions to support the vaccination campaign.

E. Sefik et al.

Inflammasome activation in infected macrophages drives COVID-19 pathology

Nature, April 2022; doi.org/10.1038/s41586-022-04802-1

Abstract

Severe COVID-19 is characterized by persistent lung inflammation, inflammatory cytokine production, viral RNA, and sustained interferon (IFN) response all of which are recapitulated and required for pathology in the SARS-CoV-2 infected MISTRG6-hACE2 humanized mouse model of COVID-19 with a human immune system^1–20. Blocking either viral replication with Remdesivir^21–23 or the downstream IFN stimulated cascade with anti-IFNAR2 in vivo in the chronic stages of disease attenuated the overactive immune-inflammatory response, especially inflammatory macrophages. Here, we show SARS-CoV-2 infection and replication in lung-resident human macrophages is a critical driver of disease. In response to infection mediated by CD16 and ACE2 receptors, human macrophages activate inflammasomes, release IL-1 and IL-18 and undergo pyroptosis thereby contributing to the hyperinflammatory state of the lungs. Inflammasome activation and its accompanying inflammatory response is necessary for lung inflammation, as inhibition of the NLRP3 inflammasome pathway reverses chronic lung pathology. Remarkably, this same blockade of inflammasome activation leads to the release of infectious virus by the infected macrophages. Thus, inflammasomes oppose host infection by SARS-CoV-2 by production of inflammatory cytokines and suicide by pyroptosis to prevent a productive viral cycle.

X. LIUet al.

SARS-CoV-2 spike protein–induced cell fusion activates the cGAS-STING pathway and the interferon response

Science Signaling, April 2022; doi: 10.1126/scisignal.abg8744

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused the unprecedented coronavirus disease 2019 (COVID-19) pandemic. Critical cases of COVID-19 are characterized by the production of excessive amounts of cytokines and extensive lung damage, which is partially caused by the fusion of SARS-CoV-2–infected pneumocytes. Here, we found that cell fusion caused by the SARS-CoV-2 spike (S) protein induced a type I interferon (IFN) response. This function of the S protein required its cleavage by proteases at the S1/S2 and the S2′ sites. We further showed that cell fusion damaged nuclei and resulted in the formation of micronuclei that were sensed by the cytosolic DNA sensor cGAS and led to the activation of its downstream effector STING. Phosphorylation of the transcriptional regulator IRF3 and the expression of IFNB, which encodes a type I IFN, were abrogated in cGAS-deficient fused cells. Moreover, infection with VSV-SARS-CoV-2 also induced cell fusion, DNA damage, and cGAS-STING–dependent expression of IFNB. Together, these results uncover a pathway underlying the IFN response to SARS-CoV-2 infection. Our data suggest a mechanism by which fused pneumocytes in the lungs of patients with COVID-19 may enhance the production of IFNs and other cytokines, thus exacerbating disease severity.

Yen HL et al.

Transmission of SARS-CoV-2 delta variant (AY.127) from pet hamsters to humans, leading to onward human-to-human transmission: a case study

Lancet. , https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8912929/pdf/main.pdf

CONTENUTO E COMMENTO : Studio che mira a dimostrare la possibile trasmissione del virus SARS-CoV-2 fra animali e uomo. Sono stati raccolti tamponi e campioni di sangue dagli animali di un negozio di animali e nel corrispondente magazzino di Hong Kong ; sno stati raccolti inoltre tampone nasofarigei o salivari di umani affetti da COVID-19 da virus delta legati epidemiologicamente al negozio di animali. La metà dei criceti siriani del negozio di animali e il 58% dei criceti siriani del rispettivo magazzino sono risultati positivi al virus. E’ stata riscontrata una corrispondenza filogenetica fra il genoma di delta riscontrato nel criceto siriano e di quello riscontrato negli esseri umani epidemiologicamente legati criceti, con tuttavia alcuni gradi di eterogeneità. Da questo studio sembra confermarsi la capacità da parte del criceto siriano di infettarsi con il virus SARS-CoV-2, di poterlo trasmettere all’uomo e di generare quindi una trasmissione interumana.

Questo lavoro rappresenta un ulteriore esempio a sostegno della teoria dello spill-over del virus SARS-CoV-2 da diverse specie animali all’uomo.

Rabalski L et al.

Zoonotic spill-over of SARS-CoV-2: mink-adapted virus in humans

 Clin Microbiol Infect.

https://www.clinicalmicrobiologyandinfection.com/action/showPdf?pii=S1198-743X%2821%2900698-4

CONTENUTO E COMMENTO : In questo studio viene riportato un possibile spill-over del virus SARS-CoV-2 da un animale all’uomo: in particolare si tratterebbe di un ceppo virale del visone che sarebbe diventato in grado di infettare l’uomo dopo circa 3 mesi di adattamento. Per l’analisi dei dati sono state utilizzate le tecnologie del sequenziamento di ultima generazione e della bioinformatica. In un soggetto umano asintomatico è stato riscontrato un ceppo del virus che, in base all’analisi filogenetica, presenta altissima analogia con il ceppo isolato nel visone, contenente tuttavia alcune mutazione che hanno reso possibile l’adattamento in una specie differente.
L’esatto ruolo delle mutazioni riscontrate nel nuovo ceppo virale non è chiaro, ma probabilmente sono funzionali ad aumentare la « fitness » virale nel nuovo ospite. Questo lavoro rappresenta una ulteriore prova a sostegno della teoria dello spill-over del virus SARS-CoV-2 da diverse specie animali all’uomo.

Markov PV et al.

Antigenic evolution will lead to new SARS-CoV-2 variants with unpredictable severity

Nat Rev Microbiol.,

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8919145/pdf/41579_2022_Article_722.pdf

CONTENUTO E COMMENTO : In questo articolo della sezione « comment » della prestigiosa rivista « Nature Reviews Microbiology » viene analizzata la relazione fra l’evoluzione antigenica del virus SARS-CoV-2 e la potenziale formazione di nuovi varianti virali in grado di generare sindromi di severità clinica imprevedibile. Secondo gli autori il concetto secondo cui l’evoluzione dei virus tenderebbe a produrre ceppi sempre meno virulenti al fine di poter aumentare la sua trasmissibilità non ha fondamento : la relativa bassa virulenza della più recente « variant-of-concern » Omicron sarebbe solamente una coincidenza. La virulenza sarebbe infatti del tutto indipendente dalla trasmissibilità del virus e pertanto potrebbero generarsi varianti virali non solo più trasmissibili ma contemporaneamente anche più aggressive. Un altro concetto da accantonare secondo gli autori sarebbe quello per cui la diffusione dell’immunità vaccinale o post-infezione garantirebbe in caso di reinfezione delle forme cliniche meno severe : l’evoluzione antigenica del virus potrebbe rendere infatti le nuove varianti in grado di evadere completamente la risposta immunitaria, dando luogo quindi a forme cliniche di invariata o superiore severità.

Le conoscenze dell’evoluzione antigenica dei virus sono ancora estremamente limitate e pertanto risulta estremamente difficile predire efficacemente quali nuove varianti potranno generarsi nel prossimo futuro e quali caratteristiche potranno avere. Dovrebbe essere attivamente promossa un’attenta e costante analisi dei meccanismi dell’evoluzione antigenica, specialmente in popolazioni bersaglio dove tale processo è massimizzato come gli immunodepressi o specie animali « permissive » in stretto contatto con l’uomo.

Zhang Y. et al.

Cross-species tropism and antigenic landscapes of circulating SARS-CoV-2 variants

Pre-print,

https://www.cell.com/cell-reports/pdf/S2211-1247(22)00302-3.pdf?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS2211124722003023%3Fshowall%3Dtrue

CONTENUTO E COMMENTO : In questo studio sono state analizzate 153 mutazioni del dominio legante il recettore della proteina spike e 11 “variant of concern” circolanti, inclusa Omicron per i loro cambiamenti antigenici e il tropismo interspecie in cellule che esprimevano 18 ortologi del recettore ACE2. E’ stato osservato che diverse mutazioni del dominio legante il recettore incrementano la capacità infettante virale in cellule che esprimono ortologi dell’ACE2 in specie diverse dall’uomo, in particolare quelle meno suscettibili al ceppo virale ancestrale. Pertanto, l’incremento del potere infettivo del virus in animali originariamente non suscettibili ad esso potrebbe incrementare il reservoir virale zoonotico, contribuendo allo spillover delle varianti dall’uomo all’animale e viceversa.

Pertanto è sempre più necessario un attento sistema di sorveglianza dei cambiamenti genici della proteina spike al fine di prevenire o quantomeno prevedere eventuali spillover fra specie diverse e generazione di nuove varianti.

Athanasios Kousathanas et al.

Whole genome sequencing reveals host factors underlying critical Covid-19

Nature, https://www.nature.com/articles/s41586-022-04576-6_reference.pdf

CONTENUTO E COMMENTO: Studio che confronta circa 7500 genomi di casi critici di infezione da Sars-CoV2 con circa 48.000 controlli al fine di identificare i fattori genetici e i meccanismi che predispongono in modo significativo ad un’infezione severa.

Sono state identificate 16 nuove associazioni, comprese le varianti all'interno dei geni coinvolti nella trasmissione del segnale dell'interferone (IL10RB, PLSCR1), nella differenziazione dei leucociti (BCL11A) e nella secrezione degli antigeni dei gruppi sanguigni (FUT2). Inoltre la ridotta espressione di una flippasi di membrana (ATP11A) e l'aumentata espressione di mucina (MUC1) erano associate allo sviluppo di una forma critica di malattia.

Queste associazioni genetiche implicano nuovi meccanismi biologici alla base dello sviluppo di Covid-19, molti dei quali possono essere suscettibili di targeting terapeutico.

Miriam Merad et al.

The immunology and immunopathology of COVID-19

Science, https://www.science.org/doi/epdf/10.1126/science.abm8108

Pekar, J E et al.

SARS-CoV-2 emergence very likely resulted from at least two zoonotic events

Pre-print , https://zenodo.org/record/6291628#.YiE8_hPMLOQ

CONTENUTO E COMMENTO : Studio sulle possibili origini del virus SARS-CoV-2. Secondo gli autori prima di febbraio 2020 sarebbero esistiti soltanto due « lineage » virali, denominati A e B. I due « lineage » sarebbero emersi nell’uomo da due differenti salti di specie. La prima trasmissione zoonotica avrebbe coinvolto il « lineage » B (quella che poi si è diffusa maggiormente nel corso della pandemia) e si sarebbe verificata a fine novembre/inizio dicembre 2019 e non prima di inizio novembre 2019, mentre l’introduzione del « lineage » A si sarebbe verificata entro poche settimane dal primo evento (« lineage » per il quale sarebbe stato identificato nel pipistrello Rhinolophus il reservoir definitivo). Pertanto, secondo gli autori dello studio, lo spill-over di SARS-CoV-2 nell’uomo e i primi casi di COVID-19 si sarebbero verificati a breve distanza di tempo l’uno dall’altro.

Tale studio sottolinea l’importanza di un apparato di sorveglianza intensiva nei confronti dei virus emergenti: tale apparato dovrebbe focalizzarsi non solo sulla rapida identificazione delle malattie umane ignote ma anche focalizzarsi sulle dinamiche degli animali selvatici, addomesticati e venduti, laddove il rischio di trasmissione di un patogeno all’uomo risulti consistente. La capacità di identificare rapidamente nuovi potenziali agenti patogeni e potenziali spill-over è infatti di fondamentale importanza per il contenimento dei patogeni con un potenziale pandemico.

Shiv Pillai

SARS-CoV-2 Vaccination Washes Away Original Antigenic Sin

Cell, Trends in Immunology , https://www.cell.com/trends/immunology/pdf/S1471-4906(22)00048-5.pdf

CONTENUTO E COMMENTO : : Commento del recente articolo del gruppo di Roltgen et al. (Immune imprinting, breadth of variant recognition, and germinal center response in human SARS-CoV-2 infection and vaccination,link:https://www.sciencedirect.com/science/article/pii/S0092867422000769?via%3Dihub) , finalizzato ad analizzare la risposta immunitaria elicitata dai vaccini autorizzati per Sars-Cov2 rispetto all’infezione naturale. In tale contesto è stata riscontrata una maggiore ampiezza della risposta anticorpale vaccino-indotta, con una capacità di legare le Spike proteins di diverse varianti del virus, a differenza di quanto riscontrato nell’infezione naturale. Una delle maggiori differenze evidenziate è legata al riscontro nell’infezione naturale di una incapacità di formare un centro germinativo dovuta all’assenza dell’espressione da parte delle T cell CD4+ helper follicolari di Bcl-6. In contrasto, in numerosi studi, sono stati riscontrati su linfonodi analizzati post vaccinazione a mRNA, dei robusti centri germinativi per almeno due mesi post-iniezione. Nello studio sopracitato è stata inoltre evidenziata la presenza della Spike protein in tali centri germinativi anche oltre i due mesi dalla vaccinazione, ponendo l’accento su un possibile ruolo di una persistente traduzione dell’mRNA della Spike alla base della lunga presenza dei centri germinativi. In tal modo la vaccinazione porta a superare il concetto di “original antigenic sin”, ovvero che gli anticorpi prodotti dopo la prima esposizione ad un antigene tendono a essere predominanti anche dopo l’esposizione ad antigeni che differiscono molto poco rispetto al primo.

Kedzierska K.; et al.

Count on us: T-cells in SARS-CoV-2 infection and vaccination

Cell Report Medicine, https://www.sciencedirect.com/science/article/pii/S2666379122000696  

CONTENUTO E COMMENTO: Studio espIorante la durata dell’immunità umorale e cellulare fino a 15 mesi dopo la diagnosi di infezione da SARS-CoV2. In questa analisi, condotta su campioni raccolti tra gennaio e giugno 2021 in Italia e Svezia, la risposta anticorpale IgG mediata ha raggiunto il suo picco dopo 15-28 giorni dall’infezione, per poi ridursi gradualmente e raggiungere il suo plateau a distanza di 6 mesi. A differenza della variante G614, i titoli di anticorpi neutralizzanti prodotti in risposta alle infezioni da variante Beta, Gamma e Delta si sono dimostrati fino a 8 volte inferiori. Per quanto riguarda l’immunità cellulare, invece, il numero delle cellule T, ma non delle cellule B, si è ridotto significativamente tra i mesi 6 e 15.

Simon-Loriere E et al.

Towards SARS-CoV-2 serotypes?

Nat Rev Microbiol. , https://www.nature.com/articles/s41579-022-00708-x.pdf

CONTENUTO E COMMENTO : Articolo della sezione “Comment” di Nature Review Microbiology sulla possibilità di considerare la variante Omicron un possibile sierotipo alternativo di virus SARS-CoV-2. L’elevato numero di mutazioni della proteina spike della variante Omicron contribuisce alle sue differenze funzionali e strutturali, in termine di fitness e di tropismo, che in parte sono responsabili della riduzione del 50-90% del rischio di ospedalizzazione e della mortalità, rispetto alla variante Delta. In virtù dei loro elevati cambiamenti a livello genico e della loro estensiva diffusione, sono state nominate attualmente cinque “Variant Of Concern” (VOC). Per quanto riguarda la VOC Omicron essa possiede tre “sublineages” (BA.1, BA.2, BA.3); tenendo anche conto delle franche variazioni biologiche, gli autori riterrebbero che Omicron meriti di essere considerata un sierotipo distinto di SARS-CoV-2. Inoltre la capacità di eludere la risposta anticorpale da precedente infezione o dalla vaccinazione accentuerebbero ulteriormente le differenze di Omicron con le altre varianti, avvalorando l’ipotesi di considerarla un sierotipo distinto.

E’ probabile che identificare nella variante Omicron un diverso sierotipo permetterebbe una più adeguata comprensione dei problemi di dignosi, terapia e prevenzione attuali della COVID-19, contribuendo alla realizzazione di test antigenici rapidi, di test molecolari, di anticorpi monoclonali e di vaccini il più possibile customizzati per il particolare sierotipo bersaglio.

Tomalka J.A. et al.

Fighting the SARS-CoV-2 pandemic requires a global approach to understanding the heterogeneity of vaccine responses

Nature, https://www.nature.com/articles/s41590-022-01130-4.pdf

CONTENUTO E COMMENTO : Focus di Nature sulla possibile evoluzione dell’approccio ai vaccini per Sars-CoV2, con una maggiore attenzione al ruolo svolto dall’immunità innata. L’attuale protezione vaccino-mediata si basa sulla risposta T-cell mediata e degli anticorpi neutralizzanti nei confronti della Spike protein del virus. In tale contesto il ruolo dell’immunità innata risulta ancora poco centrale e comincia ad essere esplorato con l’introduzione di nuovi adiuvanti. Tale punto risulta fondamentale per una futura definizione di un composto vaccinale efficace (così come gli attuali) ma che possa garantire un’immunità più longeva rispetto ai composti ad m-RNA attuali. In tale contesto, inoltre, un ruolo fondamentale nel regolare l’immunità innata ed adattativa è svolto dalla genetica del singolo individuo, da fattori come l’età, il sesso ed il microbioma. Nell’articolo viene esplorato e discusso inoltre un possibile approccio per ottimizzare l’uso dei vaccini e la loro efficacia nei pazienti immunodepressi. Anche in tale contesto appare prioritario approfondire l’azione e il modo di elicitare la risposta immunitaria innata, al fine di promuovere l’azione delle cellule B della memoria, plasma cells della memoria e cellule T staminali, al fine di migliorare l’efficacia e ridurre le dosi booster dei vaccini. In conclusione, tutti questi fattori impattano sulla diversa risposta immunitaria al vaccino nei singoli individui, con un ruolo importante svolto dal microbioma e dal metaboloma nel favorire una risposta immunitaria innata nelle fasi iniziale dell’infezione da Sars-CoV2 e riducendone la disseminazione. In conclusione, definire i meccanismi sottostanti l’immunità innata e la produzione di T cell della memoria e delle long-lived plasma cells potrà in futuro portare a un vaccino universale per il coronavirus.

Jonas Schuhenn et al.

Differential interferon-α subtypeinduced immune signatures are associatedwith suppression of SARS-CoV-2 infection

Proc Natl AcadSci U S A, https://www.pnas.org/content/pnas/119/8/e2111600119.full.pdf

CONTENUTO E COMMENTO: Gli interferoni di tipo I (IFN-I) presentano vari effetti biologici nel corso delle infezioni virali e sono stati utilizzati con successo per il trattamento delle malattie causate da virus. In questo studio è stata analizzata l'attività antivirale di tutti i sottotipi di IFNα umani contro la polmonite da SARS-CoV-2 per esplorare il loro potenziale terapeutico.

I dati forniscono un modello sistemico delle risposte antivirali mediate da IFN-I, che potrebbe aiutare a identificare gli effettori cellulari chiave su cui indirizzare nuovi approcci terapeutici contro l'infezione da SARS-CoV-2.

Stravalaci M et al.

Recognition and inhibition of SARS-CoV-2 by humoral innate immunity pattern recognition molecules

Nat Immunol. , https://www.nature.com/articles/s41590-021-01114-w.pdf

CONTENUTO E COMMENTO : Studio sulla risposta umorale dell’immunità innata, costituita da molecole che possono essere considerate veri e propri biomarker di severità della COVID-19. Vengono valutate sistemicamente le interazioni fra le « fluid-phase pattern recognition molecules” dell’immunità innata umorale e il virus SARS-CoV-2. Dall studio emerge che in particolare due molecole, la “long pentraxin 3” e la “mannose-binding lectin” (MBL), legano rispettivamente il nucleocapside la proteina spike del virus. Inoltre, dei polimorfismi genetici di alcuni loci della MBL2 sembrerebbero associati con la severità della malattia. Il riconoscimento del virus SARS-CoV-2 mediato dalla MBL sembrerebbe rivelarsi un’arma a doppio taglio: da un lato, nelle fasi iniziali della malattia, la MBL potrebbe essere implicata in un meccanismo di resistenza al virus, bloccandone l’ingresso nella cellula; dall’altro lato, nelle fasi avanzate della malattia, potrebbe contribuire all’attivazione del complemento e all’iper-attivazione della risposta immunitaria. I risultati di tale studio forniscono spunti per una valutazione comprensiva del rischio genetico di sviluppare una forma severa di malattia e spunti per implementare nuovi approcci terapeutici.

Qing X. et al

Close relatives of MERS-CoV in bats use ACE2 as their functional receptors

BioRciv, https://www.biorxiv.org/content/10.1101/2022.01.24.477490v1.full.pdf

CONTENUTO E COMMENTO : MERS-CoV appartiene alla famiglia dei Coronavirus, come anche SARS-CoV-1 e SARS-CoV-2, ma rispetto a questi ultimi due, possiede un elevatissimo “case-fatality rate”. Questo studio mira a dimostrare come il virus NeoCoV, il coronavirus più simile al MERS-CoV,  scoperto nei pipistrelli, e il virus PDF-2180-CoV, suo prossimo parente, siano in grado di legarsi efficacemente ad alcuni tipi di recettori ACE2 dei pipistrelli e dell’uomo. Gli autori mostrano come in seguito a una determinata mutazione del “receptor-binding motif”, la capacità di NeoCoV di infettare le cellule umane che esprimono il recettore ACE2 diventi estremamente efficace. Tale studio pone le basi teoriche di come possano essersi verificati e di come possano verificarsi in futuro “spillover” da una specie all’altra (in questo caso l’uomo). Nel caso in cui il virus in questione sia dotato di elevata aggressività, come nel caso dei virus MERS-CoV e simili, tali salti di specie possono rappresentare eventi dalle conseguenze drammatiche. E’ fondamentale pertanto che esistano dei validi sistemi di sorveglianza e ricerca su tali virus, per prepararsi ad eventuali nuove potenziali epidemie in futuro.

Ruobing W et al

Human airway lineages derived from pluripotent stem cells reveal the epithelial responses to SARS-CoV-2 infection

Am J Physiol Lung Cell Mol Physiol ,https://doi.org/10.1152/ajplung.00397.2021

CONTENUTO E COMMENTO: Studio degli effetti dell’infezione da SARS-CoV-2 su cellule staminali pluripotenti utilizzate per creare un modello di epitelio polmonare : si osserva nel dettaglio la risposta indotta dal virus, con produzione di interferone e altri mediatori dellìinfiammazione che si oppongono all’ingresso del virus nelle cellule.

Lippi G et al

What We Know (and Do not Know) Regarding the Pathogenesis of Pulmonary Thrombosis in COVID-19

Semin Thromb Hemost, https://doi.org/10.1055/s-0041-1742091

CONTENUTO E COMMENTO: Revisione dei meccanismi di tromboembolia polmonare caratteristici di COVID-19 : embolia polmonare vera e propria a partenza da una trombosi venosa profonda, trombosi per contiguità con un focolaio di polmonite, trombosi diffusa che coinvolge anche il polmone nell’ambito di uno stato di infiammazione generalizzato.