Host factors contributing to susceptibility to COVID-19 disease

这些研究是NIAID、NIDCR、NCI和NIAMS内部研究计划的多名主要研究人员的更广泛努力的一部分，以及与美国基因组中心/健康科学统一服务大学的研究人员的研究合作协议的一部分。我们已经组织了一个国际合作，研究在意大利中心登记的患者，该中心后来扩大到包括东亚、中东和美洲的中心。IRB批准的涉及送入样本的COVID方案是为了便于在其他没有自己的COVID方案的中心进行研究。我们已经与COVID-人类基因努力合作，这一国际合作已经发表了多篇论文。 在2022财年，我们将之前发现的I型干扰素应答中的遗传和获得性缺陷延长为严重或危重新冠肺炎的原因。我们表征了抗I型干扰素的中和自身抗体的动力学，发现这些抗体在急性感染期间动态产生，但在恢复期减少，这表明疾病的发病机制可能涉及记忆反应，这意味着在感染前检测携带此类自身抗体的个体。在与NIAID新冠肺炎联盟和COVID人类遗传学努力的各种合作中，我们还帮助表征了神经系统生物标记物和克隆性造血在呼吸道新冠肺炎中的潜在作用，以及对其他形式的SARS-CoV-2感染(MISC、围产儿)的潜在基因贡献。最后，由我们的研究小组领导的正在进行的工作正在调查双链RNA传感器的遗传变异在新冠肺炎结果中的潜在作用。

These studies have been organized as part of a broader effort among multiple principal investigators in the Intramural Research Programs of NIAID, NIDCR, NCI, and NIAMS, as well as a research collaborative agreement with investigators at the American Genome Center/Uniformed Services University of the Health Sciences. We have assembled an international collaboration to study patients enrolled at centers in Italy, which was later expanded to include centers in East Asia, the Middle East, and the Americas. An IRB-approved COVID protocol involving send-in samples was written to facilitate studies at other centers lacking their own COVID protocols. We have partnered with the COVID-Human Genetic Effort, and multiple papers have come out of this international collaboration. In FY 2022, we extended our previous discovery of genetic and acquired defects in type I IFN responses as a cause of severe or critical COVID-19. We characterized the kinetics of neutralizing autoantibodies against type I IFN and found that these were dynamically produced during acute infection but decreased during convalescence, suggesting that disease pathogenesis might involve a memory response with implications for detecting individuals with such autoantibodies before infection. In various collaborations with the NIAID COVID-19 Consortium and the COVID Human Genetic Effort, we have also assisted with the characterization of potential role of neurological biomarkers and clonal hematopoiesis in respiratory COVID-19, as well as potential genetic contribution to other forms of SARS-CoV-2 infection (MIS-C, pernio). Finally, ongoing work led by our research group is investigating the potential role of genetic variants of dsRNA sensors in COVID-19 outcome.