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      Neutralizing type‐I interferon autoantibodies are associated with delayed viral clearance and intensive care unit admission in patients with COVID‐19


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          Type‐I interferons (IFNs) mediate antiviral activity and have emerged as important immune mediators during coronavirus disease 19 (COVID‐19). Several lines of evidence suggest that impaired type‐I IFN signaling may predispose to severe COVID‐19. However, the pathophysiologic mechanisms that contribute to illness severity remain unclear. In this study, our goal was to gain insight into how type‐I IFNs influence outcomes in patients with COVID‐19. To achieve this goal, we compared clinical outcomes between 26 patients with neutralizing type‐I IFN autoantibodies (AAbs) and 192 patients without AAbs who were hospitalized for COVID‐19 at three Italian hospitals. The presence of circulating AAbs to type‐I IFNs was associated with an increased risk of admission to the intensive care unit and a delayed time to viral clearance. However, survival was not adversely affected by the presence of type‐I IFN AAbs. Our findings provide further support for the role of type‐I IFN AAbs in impairing host antiviral defense and promoting the development of critical COVID‐19 pneumonia in severe acute respiratory syndrome coronavirus 2‐infected individuals.


          Neutralizing autoantibodies to type‐I interferons predispose people to severe coronavirus disease 19 (COVID‐19). These autoantibodies are associated with admission to the intensive care unit and delayed viral clearance. However, in our study, they were not associated with increased mortality.

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          Autoantibodies against type I IFNs in patients with life-threatening COVID-19

          The genetics underlying severe COVID-19 The immune system is complex and involves many genes, including those that encode cytokines known as interferons (IFNs). Individuals that lack specific IFNs can be more susceptible to infectious diseases. Furthermore, the autoantibody system dampens IFN response to prevent damage from pathogen-induced inflammation. Two studies now examine the likelihood that genetics affects the risk of severe coronavirus disease 2019 (COVID-19) through components of this system (see the Perspective by Beck and Aksentijevich). Q. Zhang et al. used a candidate gene approach and identified patients with severe COVID-19 who have mutations in genes involved in the regulation of type I and III IFN immunity. They found enrichment of these genes in patients and conclude that genetics may determine the clinical course of the infection. Bastard et al. identified individuals with high titers of neutralizing autoantibodies against type I IFN-α2 and IFN-ω in about 10% of patients with severe COVID-19 pneumonia. These autoantibodies were not found either in infected people who were asymptomatic or had milder phenotype or in healthy individuals. Together, these studies identify a means by which individuals at highest risk of life-threatening COVID-19 can be identified. Science, this issue p. eabd4570, p. eabd4585; see also p. 404
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            Antigen-specific adaptive immunity to SARS-CoV-2 in acute COVID-19 and associations with age and disease severity

            Limited knowledge is available on the relationship between antigen-specific immune responses and COVID-19 disease severity. We completed a combined examination of all three branches of adaptive immunity at the level of SARS-CoV-2-specific CD4+ and CD8+ T cell and neutralizing antibody responses in acute and convalescent subjects. SARS-CoV-2-specific CD4+ and CD8+ T cells were each associated with milder disease. Coordinated SARS-CoV-2-specific adaptive immune responses were associated with milder disease, suggesting roles for both CD4+ and CD8+ T cells in protective immunity in COVID-19. Notably, coordination of SARS-CoV-2 antigen-specific responses was disrupted in individuals > 65 years old. Scarcity of naive T cells was also associated with ageing and poor disease outcomes. A parsimonious explanation is that coordinated CD4+ T cell, CD8+ T cell, and antibody responses are protective, but uncoordinated responses frequently fail to control disease, with a connection between ageing and impaired adaptive immune responses to SARS-CoV-2.
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              An immune-based biomarker signature is associated with mortality in COVID-19 patients

              Immune and inflammatory responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) contribute to disease severity of coronavirus disease 2019 (COVID-19). However, the utility of specific immune-based biomarkers to predict clinical outcome remains elusive. Here, we analyzed levels of 66 soluble biomarkers in 175 Italian patients with COVID-19 ranging from mild/moderate to critical severity and assessed type I IFN–, type II IFN–, and NF-κB–dependent whole-blood transcriptional signatures. A broad inflammatory signature was observed, implicating activation of various immune and nonhematopoietic cell subsets. Discordance between IFN-α2a protein and IFNA2 transcript levels in blood suggests that type I IFNs during COVID-19 may be primarily produced by tissue-resident cells. Multivariable analysis of patients’ first samples revealed 12 biomarkers (CCL2, IL-15, soluble ST2 [sST2], NGAL, sTNFRSF1A, ferritin, IL-6, S100A9, MMP-9, IL-2, sVEGFR1, IL-10) that when increased were independently associated with mortality. Multivariate analyses of longitudinal biomarker trajectories identified 8 of the aforementioned biomarkers (IL-15, IL-2, NGAL, CCL2, MMP-9, sTNFRSF1A, sST2, IL-10) and 2 additional biomarkers (lactoferrin, CXCL9) that were substantially associated with mortality when increased, while IL-1α was associated with mortality when decreased. Among these, sST2, sTNFRSF1A, IL-10, and IL-15 were consistently higher throughout the hospitalization in patients who died versus those who recovered, suggesting that these biomarkers may provide an early warning of eventual disease outcome.

                Author and article information

                Immunol Cell Biol
                Immunol Cell Biol
                Immunology and Cell Biology
                John Wiley and Sons Inc. (Hoboken )
                08 August 2021
                08 August 2021
                : 10.1111/imcb.12495
                [ 1 ] Laboratory of Clinical Immunology & Microbiology National Institute of Allergy & Infectious Diseases National Institutes of Health Bethesda MD USA
                [ 2 ] Laboratory of Human Genetics of Infectious Diseases Necker Branch INSERM U1163 Necker Hospital for Sick Children Paris France
                [ 3 ] Imagine Institute University of Paris Paris France
                [ 4 ] CREA Laboratory Diagnostic Department ASST Spedali Civili di Brescia Brescia Italy
                [ 5 ] Pediatric Department and Centro Ricerca M. Tettamanti Fondazione MBBM‐Ospedale San Gerardo University of Milano‐Bicocca Monza Italy
                [ 6 ] Department of Infectious Diseases San Gerardo Hospital University of Milano‐Bicocca Monza Italy
                [ 7 ] Department of Pediatrics Fondazione IRCCS Policlinico San Matteo University of Pavia Pavia Italy
                [ 8 ] St. Giles Laboratory of Human Genetics of Infectious Diseases Rockefeller Branch The Rockefeller University New York NY USA
                [ 9 ] Howard Hughes Medical Institute New York NY USA
                Author notes
                [*] [* ] Correspondence

                Michail S Lionakis, Laboratory of Clinical Immunology & Microbiology, National Institute of Allergy & Infectious Diseases, National Institutes of Health, Building 10, Room 12C103A, Bethesda, MD 20892, USA.

                E‐mail: lionakism@ 123456mail.nih.gov


                Equal contributors.

                Author information
                © 2021 Australian and New Zealand Society for Immunology Inc.

                This article is being made freely available through PubMed Central as part of the COVID-19 public health emergency response. It can be used for unrestricted research re-use and analysis in any form or by any means with acknowledgement of the original source, for the duration of the public health emergency.

                : 21 July 2021
                : 07 June 2021
                : 23 July 2021
                Page count
                Figures: 2, Tables: 0, Pages: 5, Words: 6040
                Funded by: Division of Intramural Research, National Institute of Allergy and Infectious Diseases , doi 10.13039/100006492;
                Funded by: Fondation pour la Recherche Médicale , doi 10.13039/501100002915;
                Award ID: EQU201903007798
                Funded by: Agence Nationale de la Recherche , doi 10.13039/501100001665;
                Award ID: ANR‐10‐IAHU‐01
                Award ID: ANR‐10‐LABX‐62‐IBEID
                Funded by: National Human Genome Research Institute , doi 10.13039/100000051;
                Award ID: U24HG008956
                Award ID: UM1HG006504
                Funded by: National Institutes of Health , doi 10.13039/100000002;
                Award ID: R01AI088364
                Funded by: National Center for Advancing Translational Sciences , doi 10.13039/100006108;
                Award ID: UL1 TR001866
                Funded by: Regione Lombardia , doi 10.13039/501100009882;
                Outstanding Observation
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                Converter:WILEY_ML3GV2_TO_JATSPMC version:6.0.7 mode:remove_FC converted:16.09.2021

                Cell biology
                immunological deficiency syndromes,infectious diseases,innate immunity,translational immunology,viral infection


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