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1.
J Exp Med ; 219(7)2022 Jul 04.
Article in English | MEDLINE | ID: covidwho-1878728

ABSTRACT

Autosomal recessive IRF7 deficiency was previously reported in three patients with single critical influenza or COVID-19 pneumonia episodes. The patients' fibroblasts and plasmacytoid dendritic cells produced no detectable type I and III IFNs, except IFN-ß. Having discovered four new patients, we describe the genetic, immunological, and clinical features of seven IRF7-deficient patients from six families and five ancestries. Five were homozygous and two were compound heterozygous for IRF7 variants. Patients typically had one episode of pulmonary viral disease. Age at onset was surprisingly broad, from 6 mo to 50 yr (mean age 29 yr). The respiratory viruses implicated included SARS-CoV-2, influenza virus, respiratory syncytial virus, and adenovirus. Serological analyses indicated previous infections with many common viruses. Cellular analyses revealed strong antiviral immunity and expanded populations of influenza- and SARS-CoV-2-specific memory CD4+ and CD8+ T cells. IRF7-deficient individuals are prone to viral infections of the respiratory tract but are otherwise healthy, potentially due to residual IFN-ß and compensatory adaptive immunity.


Subject(s)
COVID-19 , Influenza, Human , Virus Diseases , Viruses , Adult , COVID-19/genetics , Humans , Influenza, Human/genetics , SARS-CoV-2
2.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-310188

ABSTRACT

Background: The heterogeneity of COVID-19 lies within its diverse symptoms and severity, ranging from mild to lethal. Acute respiratory distress syndrome (ARDS) has been shown to be the leading cause of mortality in COVID-19 patients, characterized by a hyper cytokine storm. Autoimmunity is proposed to occur as a result of COVID-19, given the high similarity of the immune responses observed in COVID-19 and autoimmune diseases. Results Here, we investigate the level of autoimmune antibodies in COVID-19 patients with different severities. Initial screening for antinuclear antibodies (ANA) IgG revealed that 1.6% (2/126) and 4% (5/126) of ICU COVID-19 cases developed strong and moderate ANA levels, respectively. However, all the non-ICU cases (n = 273) were ANA negative. The high ANA level was confirmed by immunofluorescence (IFA) and large-scale autoantibody screening by phage immunoprecipitation-sequencing (PhIP-Seq). Indeed, the majority of the samples showed "speckled" ANA pattern by microscopy, and we demonstrate that samples of ICU patients with strong and moderate ANA levels contain autoantibody specificities that predominantly targeted proteins involved in intracellular signal transduction, metabolism, apoptotic processes, and cell death;further denoting reactivity to nuclear and cytoplasmic antigens. Conclusion Our results further support the notion of routine screening for autoimmune responses in COVID-19 patients, which might help improve disease prognosis and patient management. Further, results provide compelling evidence that ANA-positive individuals should be excluded from being donors for convalescent plasma therapy in the context of Covid-19.

3.
J Clin Immunol ; 42(3): 471-483, 2022 04.
Article in English | MEDLINE | ID: covidwho-1653615

ABSTRACT

BACKGROUND: Inborn errors of immunity (IEI) and autoantibodies to type I interferons (IFNs) underlie critical COVID-19 pneumonia in at least 15% of the patients, while the causes of multisystem inflammatory syndrome in children (MIS-C) remain elusive. OBJECTIVES: To detect causal genetic variants in very rare cases with concomitant critical COVID-19 pneumonia and MIS-C. METHODS: Whole exome sequencing was performed, and the impact of candidate gene variants was investigated. Plasma levels of cytokines, specific antibodies against the virus, and autoantibodies against type I IFNs were also measured. RESULTS: We report a 3-year-old child who died on day 56 of SARS-CoV-2 infection with an unusual clinical presentation, combining both critical COVID-19 pneumonia and MIS-C. We identified a large, homozygous loss-of-function deletion in IFNAR1, underlying autosomal recessive IFNAR1 deficiency. CONCLUSIONS: Our findings confirm that impaired type I IFN immunity can underlie critical COVID-19 pneumonia, while suggesting that it can also unexpectedly underlie concomitant MIS-C. Our report further raises the possibility that inherited or acquired dysregulation of type I IFN immunity might contribute to MIS-C in other patients.


Subject(s)
COVID-19 , Interferon Type I , Autoantibodies , COVID-19/complications , Child, Preschool , Cytokines , Humans , Receptor, Interferon alpha-beta/genetics , SARS-CoV-2 , Systemic Inflammatory Response Syndrome
4.
JCI Insight ; 6(4)2021 02 22.
Article in English | MEDLINE | ID: covidwho-1047074

ABSTRACT

Four endemic human coronaviruses (HCoVs) are commonly associated with acute respiratory infection in humans. B cell responses to these "common cold" viruses remain incompletely understood. Here we report a comprehensive analysis of CoV-specific antibody repertoires in 231 children and 1168 adults using phage immunoprecipitation sequencing. Seroprevalence of antibodies against endemic HCoVs ranged between approximately 4% and 27% depending on the species and cohort. We identified at least 136 novel linear B cell epitopes. Antibody repertoires against endemic HCoVs were qualitatively different between children and adults in that anti-HCoV IgG specificities more frequently found among children targeted functionally important and structurally conserved regions of the spike, nucleocapsid, and matrix proteins. Moreover, antibody specificities targeting the highly conserved fusion peptide region and S2' cleavage site of the spike protein were broadly cross-reactive with peptides of epidemic human and nonhuman coronaviruses. In contrast, an acidic tandem repeat in the N-terminal region of the Nsp3 subdomain of the HCoV-HKU1 polyprotein was the predominant target of antibody responses in adult donors. Our findings shed light on the dominant species-specific and pan-CoV target sites of human antibody responses to coronavirus infection, thereby providing important insights for the development of prophylactic or therapeutic monoclonal antibodies and vaccine design.


Subject(s)
Antibodies, Viral/isolation & purification , Common Cold/virology , Coronavirus Infections/immunology , Coronavirus/immunology , Endemic Diseases , Adult , Antibodies, Viral/blood , Antibodies, Viral/immunology , Antibody Specificity , Antigens, Viral/blood , Antigens, Viral/immunology , Child , Child, Preschool , Common Cold/blood , Common Cold/epidemiology , Common Cold/immunology , Coronavirus/isolation & purification , Coronavirus Infections/blood , Coronavirus Infections/epidemiology , Coronavirus Infections/virology , Cross Reactions , Epitopes, B-Lymphocyte/blood , Epitopes, B-Lymphocyte/immunology , Female , Humans , Male , Middle Aged , Protein Domains/immunology , Retrospective Studies , Seroepidemiologic Studies , Viral Proteins/immunology
5.
Science ; 370(6515)2020 10 23.
Article in English | MEDLINE | ID: covidwho-796722

ABSTRACT

Clinical outcome upon infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ranges from silent infection to lethal coronavirus disease 2019 (COVID-19). We have found an enrichment in rare variants predicted to be loss-of-function (LOF) at the 13 human loci known to govern Toll-like receptor 3 (TLR3)- and interferon regulatory factor 7 (IRF7)-dependent type I interferon (IFN) immunity to influenza virus in 659 patients with life-threatening COVID-19 pneumonia relative to 534 subjects with asymptomatic or benign infection. By testing these and other rare variants at these 13 loci, we experimentally defined LOF variants underlying autosomal-recessive or autosomal-dominant deficiencies in 23 patients (3.5%) 17 to 77 years of age. We show that human fibroblasts with mutations affecting this circuit are vulnerable to SARS-CoV-2. Inborn errors of TLR3- and IRF7-dependent type I IFN immunity can underlie life-threatening COVID-19 pneumonia in patients with no prior severe infection.


Subject(s)
Coronavirus Infections/genetics , Coronavirus Infections/immunology , Interferon Type I/immunology , Loss of Function Mutation , Pneumonia, Viral/genetics , Pneumonia, Viral/immunology , Adolescent , Adult , Aged , Aged, 80 and over , Alleles , Asymptomatic Infections , Betacoronavirus , COVID-19 , Child , Child, Preschool , Female , Genetic Loci , Genetic Predisposition to Disease , Humans , Infant , Interferon Regulatory Factor-7/deficiency , Interferon Regulatory Factor-7/genetics , Male , Middle Aged , Pandemics , Receptor, Interferon alpha-beta/deficiency , Receptor, Interferon alpha-beta/genetics , SARS-CoV-2 , Toll-Like Receptor 3/deficiency , Toll-Like Receptor 3/genetics , Young Adult
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