Inborn errors of immunity in patients with life-threatening COVID-19

危及生命的 COVID-19 患者先天性免疫缺陷

• 批准号: 10449276
• 负责人: Jean-Laurent Casanova
• 金额: $ 75.25万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-12 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10449276
• 关键词: 2019-nCoV; Age; Autoantibodies; Autoimmune; B-Lymphocytes; Biological; Biological Assay; Bloch Sulzberger syndrome; CD4 Positive T Lymphocytes; COVID-19; COVID-19 patient; COVID-19 pneumonia; Case Study; Categories; Cell Line; Cell model; Cells; Clinical; Communicable Diseases; Custom; Data; Defect; Disease; Epidemiologic Factors; Ethnic Origin; Fatality rate; Fibroblasts; Future; Gender; Genes; Genetic; Genetic Heterogeneity; Genetic study; Hereditary Disease; Human; Human Genetics; IFNAR1 gene; Immunity; Impairment; In Vitro; Individual; Infection; Influenza; Interferon Type I; Interferon-alpha; Interferon-beta; Interferons; International; Leucine-Rich Repeat; Life; Link; Medical; Monoclonal Antibodies; Mutation; Nebulizer; Other Genetics; Pathogenesis; Pathway interactions; Patients; Penetrance; Phenocopy; Plasmapheresis; Production; Proteins; Recording of previous events; Reporting; Rice; Risk; SARS-CoV-2 immunity; SARS-CoV-2 infection; Serum; Severities; Susceptibility Gene; T-Cell Development; TLR3 gene; Testing; Universities; Variant; Viral; Viral Physiology; Virulence; Virus; Virus Diseases; Woman; X Inactivation; aged; base; cohort; comorbidity; coronavirus disease; genomic data; influenza pneumonia; loss of function; male; men; multiplex assay; novel diagnostics; novel therapeutic intervention; programs; recruit; response; sensor; severe COVID-19; subcutaneous; viral RNA

Project Summary There is immense interindividual clinical variability in humans infected with SARS-CoV-2, ranging from silent infection to lethal COVID-19. The first breakthrough to crack this enigma came from the field of inborn errors of immunity (IEI). In an international cohort of 659 patients, we reported 23 patients with IEIs at eight influenza susceptibility loci that govern TLR3- and IRF7-dependent type I interferon (IFN) immunity (3.5%), including four unrelated patients with autosomal recessive IRF7 or IFNAR1 deficiency. We also reported an additional 101 patients with neutralizing autoantibodies (auto-Abs) against type I IFN (10.2% of 987), who were auto-immune phenocopies of the patients with IEI. Interestingly, 94% of the patients with auto-Ab against type I IFN were men, and one of the six sick women had X-linked dominant incontinentia pigmenti (IP), suggesting X-linked inheritance in at least some of the patients. Collectively, these patients account for about 13.5% of life-threatening COVID- 19 cases studied. We now hypothesize that other IEI that result in abnormal (i) production or amplification of type I IFN, (ii) activity of soluble type I IFNs (via neutralizing auto-Abs), or (iii) response to type I IFN (in terms of interferon stimulated gene (ISG) activity), can underlie life-threatening COVID-19 in other patients. To tackle these three specific aims, we benefit from an international recruitment from the COVID Human Genetic Effort (https://www.covidhge.com). Our preliminary data are very strong. First, we have found 215 patients with predicted loss-of-function (pLOF) variants at 157 loci associated with production or amplification of type I IFN, including one patient homozygous for a pLOF variants in NLRC3, two patients heterozygous for pLOF variants in DDX58/RIG-I, and six patients heterozygous for pLOF variants in subtypes of type I or III IFNs. Second, among patients with auto-Ab against type I IFN, we identified a patient hemizygous for a pLOF in X-linked SASH3. In addition, we found that 25% of patients with IP, which is associated with severely skewed X-inactivation, have auto-Ab against type I IFN, further suggesting an X-linked basis of auto-Ab to type I IFN production. Third, we found 24 patients with pLOF variants in 18 ISGs. We have shown that the international path-breaking program we established in only 6 months is highly efficient, as it resulted in a paradigm-shifting discovery. Our new program will benefit from this momentum. Our future discoveries of new inborn errors of type I IFN immunity underlying life-threatening COVID-19 pneumonia will pave the way for new diagnostic and therapeutic strategies to better manage patients infected with SARS-CoV-2 at risk of severe disease. Selected patients may benefit from subcutaneous or nebulized IFN-a or IFN-b (defect in type I IFN production or amplification), plasmapheresis and/or B cell depletion (neutralizing auto-Abs against type I IFNs), or other therapies, including mAbs against SARS-CoV-2 (defects of ISGs).

项目摘要 感染SARS-COV-2的人类有巨大的个体临床变异性，从沉默到 感染致命的covid-19。破解这种谜的第一个突破来自天生错误的领域 免疫力（IEI）。在一组659名患者的国际队列中，我们报告了23例IEI患者在8个流感中 控制TLR3-和IRF7依赖性I类干扰素（IFN）免疫（3.5％）的敏感基因座，包括四个 常染色体隐性IRF7或IFNAR1缺乏症患者无关。我们还报告了另外101 对I型IFN（987的10.2％）中和自身抗体（自动抗体）的患者（自动免疫） IEI患者的表演。有趣的是，有94％的自动AB患者针对I型IFN是男性 六个病女性中的一位具有X连锁的占主导地位的色素（IP），提示X连接的继承 至少有一些患者。总的来说，这些患者约占威胁生命的covid-的13.5％ 研究了19例。现在，我们假设其他IEI导致异常（i）产生或放大 I型IFN，（ii）可溶性I型IFN的活动（通过中和自动-ABS）或（iii）对I型IFN的响应（以 干扰素刺激的基因（ISG）活性），其他患者的危及生命的covid是基础的。要解决 这三个特定的目标，我们受益于联想人类遗传努力的国际招聘 （https://www.covidhge.com）。我们的初步数据非常强。首先，我们发现了215名患者 预测功能丧失（PLOF）变体处于157个基因座，与I型IFN的生产或扩增相关 包括一名N​​LRC3中植物变体的纯合子的患者，两名患者杂合植物变体的变体 在DDX58/rig-I中，六名患者在I型或III型IFN的亚型中的plof变体杂合子。第二，中间 针对I型IFN的自动AB的患者，我们确定了X连锁SASH3中plof的患者半合子。在 此外，我们发现25％的IP患者与严重偏斜的X灭活有关 对I型IFN的自动AB，进一步建议自动AB的X连锁基础I型IFN生产。第三，我们 在18个ISG中发现了24例plof变体的患者。我们已经证明了国际破裂计划 我们在仅6个月内建立了高效，因为这导致了范式转移发现。我们的新 计划将从这一势头中受益。我们未来对新先生的IFN免疫力的发现 潜在的威胁生命的Covid-19肺炎将为新的诊断和治疗策略铺平道路 更好地管理感染患有严重疾病风险的SARS-COV-2的患者。选定的患者可能会受益 从皮下或雾化的IFN-A或IFN-B（I型IFN产生或扩增中的缺陷），血浆置换 和/或B细胞耗竭（对I型IFN的自动AB中和）或其他疗法，包括对抗的mAb SARS-COV-2（ISG的缺陷）。