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

基本信息

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
项目类别：
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

项目摘要

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).

项目概要感染 SARS-CoV-2 的人类存在巨大的个体间临床差异，从无症状到无症状感染致命的 COVID-19。破解这个谜团的第一个突破来自先天性错误领域免疫（IEI）。在一个由 659 名患者组成的国际队列中，我们报告了 23 名患者在 8 次流感期间出现 IEI 控制 TLR3 和 IRF7 依赖性 I 型干扰素 (IFN) 免疫的易感位点 (3.5%)，包括四个患有常染色体隐性遗传 IRF7 或 IFNAR1 缺陷的无关患者。我们还报告了另外 101 具有针对 I 型 IFN 的中和自身抗体 (auto-Abs) 的患者（987 名患者中的 10.2%），这些患者具有自身免疫性 IEI 患者的表型。有趣的是，94% 的携带 I 型 IFN 自身抗体的患者是男性，六名患病女性中的一名患有 X 连锁显性色素失禁 (IP)，表明 X 连锁遗传至少在某些患者中。总的来说，这些患者约占危及生命的新冠肺炎患者的 13.5%。研究了19个案例。我们现在假设其他 IEI 导致异常 (i) 产生或扩增 I 型干扰素，(ii) 可溶性 I 型干扰素的活性（通过中和自身抗体），或 (iii) 对 I 型干扰素的反应（就干扰素刺激基因 (ISG) 活性）可能是危及其他患者生命的 COVID-19 的基础。解决这三个具体目标，我们受益于新冠人类基因努力的国际招募（https://www.covidhge.com）。我们的初步数据非常有力。首先，我们发现了215名患者预测与 I 型 IFN 的产生或扩增相关的 157 个位点的功能丧失 (pLOF) 变异，包括一名 NLRC3 中 pLOF 变异纯合的患者，两名 pLOF 变异杂合的患者 DDX58/RIG-I，以及 6 名 I 型或 III 型 IFN 亚型 pLOF 变异杂合患者。二、其中在患有 I 型 IFN 自身抗体的患者中，我们鉴定出一名 X 连锁 SASH3 中 pLOF 半合子的患者。在此外，我们发现 25% 的 IP 患者（与严重偏斜的 X 失活相关）患有针对 I 型 IFN 的自身抗体，进一步表明针对 I 型 IFN 产生的自身抗体存在 X 连锁基础。第三，我们在 18 个 ISG 中发现了 24 名具有 pLOF 变异的患者。我们已经证明了国际开创性的计划我们仅用了 6 个月就建立了高效的团队，因为它带来了范式转变的发现。我们的新计划将从这一势头中受益。我们未来对 I 型干扰素免疫的新先天性缺陷的发现潜在威胁生命的 COVID-19 肺炎将为新的诊断和治疗策略铺平道路更好地管理患有严重疾病风险的 SARS-CoV-2 感染患者。选定的患者可能会受益来自皮下或雾化的 IFN-a 或 IFN-b（I 型 IFN 产生或扩增缺陷）、血浆置换和/或 B 细胞耗竭（中和针对 I 型 IFN 的自身抗体），或其他疗法，包括针对 I 型 IFN 的单克隆抗体 SARS-CoV-2（ISG 的缺陷）。