Host factors contributing to susceptibility to COVID-19 disease

这些研究是NIAID，NIDCR，NCI和NIAMS的校内研究计划中多个主要研究者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。我们已经组织了一项国际合作，研究在意大利中心入组的患者，后来扩展到包括东亚、中东和美洲的中心。IRB批准的COVID方案涉及发送样本，以便于在其他缺乏自己的COVID方案的中心进行研究。我们与COVID-人类遗传努力合作，并通过这种国际合作发表了多篇论文。 于2023财年，我们扩展了先前发现的I型IFN反应的遗传和后天缺陷是导致严重或危重COVID-19的原因。在与NIAID COVID-19 Consortium和COVID Human Genetic Effort的各种合作中，我们还为SARS-CoV-2感染后儿童多系统炎症综合征（MIS-C）的新单基因形式的鉴定做出了贡献。通过这些大型的国际合作努力，发现儿童在OAS 1，OAS 2或RNASEL基因中具有罕见的双等位基因功能丧失突变。这些突变导致促炎细胞因子增加，从而导致疾病。这一发现可以提高对有发生SARS-CoV-2感染罕见并发症风险的儿童的分子诊断。他们还提供了科学的理论基础，分子靶向的途径，其失调是这种情况的核心。最后，由我们的研究小组领导的正在进行的工作正在调查dsRNA传感器的遗传变体在COVID-19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 2023, we extended our previous discovery of genetic and acquired defects in type I IFN responses as a cause of severe or critical COVID-19. In various collaborations with the NIAID COVID-19 Consortium and the COVID Human Genetic Effort, we have also contributed to the identification of new monogenic forms of multisystem inflammatory syndrome in children (MIS-C) following SARS-CoV-2 infection. Through these large international collaborative efforts, children were discovered with rare biallelic loss-of-function mutations in the OAS1, OAS2, or RNASEL genes. These mutations result in increased proinflammatory cytokines leading to disease. This discovery can improve molecular diagnosis of children at risk for developing a rare complication of SARS-CoV-2 infection. They also provide scientific rationale for molecular targeting of a pathway whose dysregulation is central to this condition. Finally, ongoing work led by our research group is investigating the potential role of genetic variants of dsRNA sensors in COVID-19 outcome.