Host factors contributing to susceptibility to COVID-19 disease

导致对 COVID-19 疾病易感性的宿主因素

• 批准号: 10927930
• 负责人: Helen Su
• 金额: $ 47.84万
• 依托单位: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10927930
• 关键词: 2019-nCoV; Acute; Affect; Agreement; American; Americas; Biochemical; COVID-19; COVID-19 susceptibility; Child; Collaborations; Complication; Convalescence; Defect; Disease; Double-Stranded RNA; Family member; Far East; Genes; Genetic; Genetic Determinism; Genome; Health Sciences; Human; Human Genetics; Immune; Immune response; In Vitro; Individual; Inflammatory; Innate Immune Response; Institutional Review Boards; Integration Host Factors; Interferons; International; Intramural Research Program; Italy; Knowledge; Life; Loss of Heterozygosity; Middle East; Molecular; Molecular Diagnosis; Molecular Target; Multisystem Inflammatory Syndrome in Children; Mutation; National Institute of Allergy and Infectious Disease; National Institute of Arthritis, and Musculoskeletal, and Skin Diseases; National Institute of Dental and Craniofacial Research; Outcome; Paper; Pathogenesis; Pathway interactions; Patients; Persons; Population Genetics; Predisposition; Principal Investigator; Program Research Project Grants; Protocols documentation; Recording of previous events; Research; Research Personnel; Risk; Role; SARS-CoV-2 infection; Sampling; Susceptibility Gene; Therapeutic Intervention; University Health Services; Validation; Variant; Work; Writing; adaptive immune response; comorbidity; consanguineous family; coronavirus disease; cytokine; genetic approach; genetic variant; improved; loss of function mutation; molecular targeted therapies; participant enrollment; post SARS-CoV-2 infection; respiratory; response; sensor; severe COVID-19; variant of interest; young adult

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.

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2023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。在与NIAID新冠肺炎联盟和COVID人类遗传学工作的各种合作中，我们还为识别感染SARS-CoV-2后的儿童多系统炎症综合征(MISC)的新单基因形式做出了贡献。通过这些大型国际合作努力，儿童被发现在OAS1、OAS2或RNASL基因中存在罕见的双等位功能丧失突变。这些突变会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患有SARS-CoV-2感染罕见并发症的儿童的分子诊断。他们还提供了分子靶向的分子靶向的途径，其失调是这种情况的中心。最后，由我们的研究小组领导的正在进行的工作正在调查双链RNA传感器的遗传变异在新冠肺炎结果中的潜在作用。

项目成果

Clonal hematopoiesis is not significantly associated with COVID-19 disease severity.

• DOI: 10.1182/blood.2022015721
• 发表时间: 2022-10-06
• 期刊: BLOOD
• 影响因子: 20.3
• 作者: Zhou, Yifan;Shalhoub, Ruba;Rogers, Stephanie N.;Yu, Shiqin;Gu, Muxin;Fabre, Margarete A.;Quiros, Pedro M.;Shin, Tae-Hoon;Diangson, Arch;Deng, Wenhan;Anand, Shubha;Lu, Wenhua;Cullen, Matthew;Godfrey, Anna L.;Preller, Jacobus;Hadjadj, Jerome;Jouanguy, Emmanuelle;Cobat, Aurelie;Abel, Laurent;Rieux-Laucat, Frederic;Terrier, Benjamin;Fischer, Alain;Novik, Lara;Gordon, Ingelise J.;Strom, Larisa;Gaudinski, Martin R.;Lisco, Andrea;Sereti, Irini;Gniadek, Thomas J.;Biondi, Andrea;Bonfanti, Paolo;Imberti, Luisa;Dalgard, Clifton L.;Zhang, Yu;Dobbs, Kerry;Su, Helen C.;Notarangelo, Luigi D.;Wu, Colin O.;Openshaw, Peter J. M.;Semple, Malcolm G.;Mallat, Ziad;Baillie, Kenneth;Dunbar, Cynthia E.;Vassiliou, George S.
• 通讯作者: Vassiliou, George S.

Deep immune profiling uncovers novel associations with clinical phenotypes of multisystem inflammatory syndrome in children (MIS-C).

深度免疫分析揭示了与儿童多系统炎症综合征 (MIS-C) 临床表型的新关联。

• DOI: 10.1136/ard-2022-223269
• 发表时间: 2023
• 期刊: Annals of the rheumatic diseases
• 影响因子: 27.4
• 作者: Redmond,ChristopherJohn;Kitakule,MosesM;Son,Aran;Sylvester,McKella;Sacco,Keith;Delmonte,Ottavia;Licciardi,Francesco;Castagnoli,Riccardo;Poli,MCecilia;Espinoza,Yasmin;Astudillo,Camila;Weber,SarahE;MontealegreSanchez,GinaA;Ba
• 通讯作者: Ba

Temporal Dynamics of Anti-Type 1 Interferon Autoantibodies in Patients With Coronavirus Disease 2019.

• DOI: 10.1093/cid/ciab1002
• 发表时间: 2022-08-24
• 期刊: Clinical infectious diseases : an official publication of the Infectious Diseases Society of America
• 作者: Shaw ER;Rosen LB;Cheng A;Dobbs K;Delmonte OM;Ferré EMN;Schmitt MM;Imberti L;Quaresima V;Lionakis MS;Notarangelo LD;Holland SM;Su HC
• 通讯作者: Su HC