Browsing by Author "Uddin, Mohammed J"

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Autoantibodies against type I IFNs in patients with life-threatening COVID-19
(2020) Uddin, Mohammed J
Introduction: Three risk factors for life-threatening coronavirus disease 2019 (COVID-19) pneumonia have been identified— being male, being elderly, or having other medical conditions—but these risk factors cannot explain why critical disease remains relatively rare in any given epidemiological group. Given the rising toll of the COVID-19 pandemic in terms ofmorbidity andmortality, understanding the causes and mechanisms of life-threatening COVID-19 is crucial. Rationale: B cell autoimmune infectious phenocopies of three inborn errors of cytokine immunity exist, in which neutralizing autoantibodies (auto-Abs) against interferon-g (IFN-g) (mycobacterial disease), interleukin-6 (IL-6) (staphylococcal disease), and IL-17A and IL-17F (mucocutaneous candidiasis) mimic the clinical phenotypes of germline mutations of the genes that encode the corresponding cytokines or receptors. Human inborn errors of type I IFNs underlie severe viral respiratory diseases. Neutralizing auto-Abs against type I IFNs, which have been found in patients with a few underlying noninfectious conditions, have not been unequivocally shown to underlie severe viral infections. While searching for inborn errors of type I IFN immunity in patients with life-threatening COVID-19 pneumonia, we also tested the hypothesis that neutralizing auto-Abs against type I IFNs may underlie critical COVID-19. We searched for auto-Abs against type I IFNs in 987 patients hospitalized for life-threatening COVID- 19 pneumonia, 663 asymptomatic or mildly affected individuals infected with SARSCoV- 2, and 1227 healthy controls from whom samples were collected before the COVID- 19 pandemic. Results: At least 101 of 987 patients (10.2%) with life-threatening COVID-19 pneumonia had neutralizing immunoglobulin G (IgG) auto-Abs against IFN-w (13 patients), against the 13 types of IFN-a (36), or against both (52) at the onset of critical disease; a few also had auto-Abs against the other three individual type I IFNs. These auto-Abs neutralize high concentrations of the corresponding type I IFNs, including their ability to block SARSCoV- 2 infection in vitro. Moreover, all of the patients tested had low or undetectable serum IFN-a levels during acute disease. These auto- Abs were present before infection in the patients tested and were absent from 663 individualswith asymptomatic ormild SARSCoV- 2 infection (P < 10−16). They were present in only 4 of 1227 (0.33%) healthy individuals (P < 10−16) before the pandemic. The patients with auto-Abs were 25 to 87 years old (half were over 65) and of various ancestries. Notably, 95 of the 101 patients with auto-Abs were men (94%). Conclusion: ABcell autoimmunephenocopy of inborn errors of type I IFN immunity accounts for life-threatening COVID-19 pneumonia in at least 2.6% of women and 12.5%ofmen. In these patients, adaptive autoimmunity impairs innate and intrinsic antiviral immunity. These findings provide a first explanation for the excess of men among patients with life threatening COVID-19 and the increase in risk with age. They also provide a means of identifying individuals at risk of developing life-threatening COVID-19 and ensuring their enrolment in vaccine trials. Finally, they pave the way for prevention and treatment, including plasmapheresis, plasmablast depletion, and recombinant type I IFNs not targeted by the auto-Abs (e.g., IFN-b).
Inborn errors of type I IFN immunity in patients with life-threatening COVID-19
(2020) Uddin, Mohammed J
Introduction: Clinical outcomes of human severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection range from silent infection to lethal coronavirus disease 2019 (COVID-19). Epidemiological studies have identified three risk factors for severe disease: being male, being elderly, and having other medical conditions. However, interindividual clinical variability remains huge in each demographic category. Discovering the root cause and detailed molecular, cellular, and tissue- and body-level mechanisms underlying life-threatening COVID-19 is of the utmost biological and medical importance. Rationale: We established the COVID Human Genetic Effort (www.covidhge.com) to test the general hypothesis that life-threatening COVID-19 in some or most patients may be caused by monogenic inborn errors of immunity to SARS-CoV-2 with incomplete or complete penetrance. We sequenced the exome or genome of 659 patients of various ancestries with life-threatening COVID-19 pneumonia and 534 subjects with asymptomatic or benign infection.We tested the specific hypothesis that inborn errors of Toll-like receptor 3 (TLR3)– and interferon regulatory factor 7 (IRF7)– dependent type I interferon (IFN) immunity that underlie life-threatening influenza pneumonia also underlie life threatening COVID-19 pneumonia.Weconsidered three loci identified as mutated in patients with life-threatening influenza: TLR3, IRF7, and IRF9. We also considered 10 loci mutated in patients with other viral illnesses but directly connected to the three core genes conferring influenza susceptibility: TICAM1/TRIF, UNC93B1, TRAF3, TBK1, IRF3, and NEMO/IKBKG from the TLR3-dependent type I IFN induction pathway, and IFNAR1, IFNAR2, STAT1, and STAT2 from the IRF7- and IRF9-dependent type I IFN amplification pathway. Finally, we considered various modes of inheritance at these 13 loci. Results: We found an enrichment in variants predicted to be loss-of-function (pLOF), with a minor allele frequency <0.001, at the 13 candidate loci in the 659 patients with life threatening COVID-19 pneumonia relative to the 534 subjects with asymptomatic or benign infection (P = 0.01). Experimental tests for all 118 rare nonsynonymous variants (including both pLOF and other variants) of these 13 genes found in patients with critical disease identified 23 patients (3.5%), aged 17 to 77 years, carrying 24 deleterious variants of eight genes. These variants underlie autosomal-recessive (AR) deficiencies (IRF7 and IFNAR1) and autosomal dominant (AD) deficiencies (TLR3, UNC93B1, TICAM1, TBK1, IRF3, IRF7, IFNAR1, andIFNAR2) in four and 19 patients, respectively. These patients had never been hospitalized for other life-threatening viral illness. Plasmacytoid dendritic cells from IRF7-deficient patients produced no type I IFN on infection with SARS-CoV-2, and TLR3−/−, TLR3+/−, IRF7−/−, and IFNAR1−/− fibroblasts were susceptible to SARS-CoV-2 infection in vitro. Conclusion: At least 3.5% of patients with life threatening COVID-19 pneumonia had known (AR IRF7 and IFNAR1 deficiencies or AD TLR3, TICAM1, TBK1, and IRF3 deficiencies) or new (AD UNC93B1, IRF7, IFNAR1, and IFNAR2 deficiencies) genetic defects at eight of the 13 candidate loci involved in the TLR3- and IRF7-dependent induction and amplification of type I IFNs. This discovery reveals essential roles for both the double-stranded RNA sensor TLR3 and type I IFN cell-intrinsic immunity in the control of SARS-CoV-2 infection. Type I IFN administration may be of therapeutic benefit selected patients, at least early in the course of SARS-CoV-2 infection.
Vaccine breakthrough hypoxemic COVID-19 pneumonia in patients with auto-Abs neutralizing type I IFNs
(2024-08) Uddin, Mohammed J
Abstract Life-threatening "breakthrough" cases of critical COVID-19 are attributed to poor or waning antibody (Ab) response to SARS-CoV-2 vaccines in individuals already at risk. Preexisting auto-Abs neutralizing type I IFNs underlie at least 15% of critical COVID-19 pneumonia cases in unvaccinated individuals; their contribution to hypoxemic breakthrough cases in vaccinated people is unknown. We studied a cohort of 48 individuals (aged 20 to 86 years) who received two doses of a messenger RNA (mRNA) vaccine and developed a breakthrough infection with hypoxemic COVID-19 pneumonia 2 weeks to 4 months later. Ab levels to the vaccine, neutralization of the virus, and auto-Abs to type I IFNs were measured in the plasma. Forty-two individuals had no known deficiency of B cell immunity and a normal Ab response to the vaccine. Among them, 10 (24%) had auto-Abs neutralizing type I IFNs (aged 43 to 86 years). Eight of these 10 patients had auto-Abs neutralizing both IFN-α2 and IFN-ω, whereas two neutralized IFN-ω only. No patient neutralized IFN-β. Seven neutralized type I IFNs at 10 ng/ml and three at 100 pg/ml only. Seven patients neutralized SARS-CoV-2 D614G and Delta efficiently, whereas one patient neutralized Delta slightly less efficiently. Two of the three patients neutralizing only type I IFNs at 100 pg/ml neutralized both D614G and Delta less efficiently. Despite two mRNA vaccine inoculations and the presence of circulating Abs capable of neutralizing SARS-CoV-2, auto-Abs neutralizing type I IFNs may underlie a notable proportion of hypoxemic COVID-19 pneumonia cases, highlighting the importance of this particularly vulnerable population.