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: 10278180
• 负责人: Jean-Laurent Casanova
• 金额: $ 76.28万
• 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/10278180
• 关键词: 2019-nCoV; Age; Antiviral Agents; 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 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 在感染SARS-CoV-2的人类中，存在巨大的个体间临床变异性， 感染到致命的COVID-19。破解这个谜团的第一个突破来自先天性缺陷领域， 免疫力（IEI）。在一个659例患者的国际队列中，我们报告了23例发生IEI的患者， 控制TLR 3和IRF 7依赖性I型干扰素（IFN）免疫的易感基因座（3.5%），包括4个 常染色体隐性IRF 7或IFNAR 1缺陷的无关患者。我们还报告了另外101起 有抗I型IFN的中和自身抗体（自身抗体）的患者（10.2%/987），他们是自身免疫性的 IEI患者的表型。有趣的是，94%的具有抗I型IFN的自身抗体的患者是男性， 6名患病妇女中有1名患有X连锁显性色素失禁（IP），提示X连锁遗传 至少在一些病人身上。总体而言，这些患者约占危及生命的COVID-19的13.5%。 研究了19个病例。我们现在假设，其他IEI，导致异常（i）生产或扩增 I型IFN，（ii）可溶性I型IFN的活性（通过中和自身抗体），或（iii）对I型IFN的应答（根据 干扰素刺激基因（ISG）活性），可能是其他患者危及生命的COVID-19的基础。解决 这三个具体目标，我们受益于COVID人类遗传努力的国际招聘 （网址：）。www.covidhge.com我们的初步数据非常有力。首先，我们发现215名患者 在与I型IFN的产生或扩增相关的157个基因座处预测的功能丧失（pLOF）变体， 包括一名NLRC 3中pLOF变体纯合的患者，两名pLOF变体杂合的患者， 在DDX 58/RIG-I中，以及6名I型或III型IFN亚型中pLOF变体杂合的患者。第二，在 我们在一名患有抗I型IFN自身抗体的患者中，发现了一名X连锁SASH 3中pLOF的半合子患者。在 此外，我们发现，25%的IP患者，这是与严重偏斜X失活， 针对I型IFN的自身抗体，进一步表明针对I型IFN的自身抗体产生的X连锁基础。三是 在18个ISG中发现了24名pLOF变异患者。我们已经证明，国际开创性的计划， 我们在短短6个月内建立的是高效的，因为它导致了一个范式转变的发现。我们的新 该计划将受益于这一势头。新的I型干扰素免疫缺陷的发现 潜在的危及生命的COVID-19肺炎将为新的诊断和治疗策略铺平道路 更好地管理有严重疾病风险的SARS-CoV-2感染患者。部分患者可能受益 来自皮下或雾化IFN-α或IFN-β（I型IFN产生或扩增缺陷），血浆置换 和/或B细胞耗竭（针对I型IFN的中和自身抗体），或其它疗法，包括针对 SARS-CoV-2（ISG缺陷）。