GENOMIC APPROACHES TO UNDERSTAND DISEASE SUSCEPTIBILITY AND PATHOGENESIS OF SARS-COV-2

总体项目摘要 2019年12月在中国首次发现的新型冠状病毒SARS-CoV-2现已蔓延 在全球德克萨斯州休斯顿的德克萨斯医疗中心是美国第四大城市，也是美国前十名之一。 种族多样性，对这一流行病采取了积极的早期应对措施，主要侧重于急性护理。内 贝勒医学院，TMC -传染病基因组中心（TMC-GCID）计划的成员 （https：//gob.research.bcm.edu/overview）正在利用现有的基础设施， 与临床和社区测试相关联的强大样本收集流，以表征SARS-CoV-2 毒力和易感性。该申请要求对TMC-GCID进行补充资助 帮助支持SARS-CoV-2社区范围的监测，完成病毒基因组测序，鼻咽 微生物组分析和靶向宿主遗传分析。该补充的主要目标是 通过基础科学家和医生科学家组成的多学科综合团队的协作努力实现 具有良好的合作记录，并且已经实现了TMC-GCID的主要目标。的 我们的GCID补充的总体目标是研究SARS-CoV-2感染的生物学，宿主和 与疾病相关的微生物遗传学，并满足社区需求，特别是 服务不足的社区，通过以下目标：i）扩大业务紧急使用 符合授权（EUA-）和IRB的COVID-19 qPCR筛查/监测计划， 在线登记和同意以及符合HIPAA的结果返回，ii）排序和分析 从TMC和周围收集的感染个体的全长SARS-CoV-2基因组 iii）识别预测COVID-19疾病严重程度的微生物共定植/共感染，和/或 iv）关于病毒滴度、疾病严重性表征宿主遗传变异，和 COVID-19阳性患者的结局，包括人类白细胞抗原（HLA）的多态性， 血管紧张素转换酶2（ACE 2）和自然杀伤细胞免疫球蛋白样受体（KIR） 地区该补充将利用尖端的高通量测序策略， 由TMC-GCID测序技术（ST）核心提供的技术，在生成发现，数据， 工具和试剂，这些工具和试剂将通过 TMC-GCID数据管理分析和资源传播（DMARD）核心。结果将是一个 SARS-CoV-2感染中宿主和微生物的综合遗传图谱，将揭示病原体遗传 与个体宿主反应表型相关的变异， 治疗和诊断，不仅是针对SARS-CoV-2，而且是针对我们已经发现的其他大流行威胁， 被观察到深刻地改变了我们周围的世界。

OVERALL PROJECT SUMMARY The novel coronavirus, SARS-CoV-2, that was first detected in China in December 2019 has now spread globally. The Texas Medical Center in Houston, TX, the fourth largest city in the US, and among the top 10 in racial diversity, mounted an aggressive early response to the pandemic, primarily focused on acute care. Within Baylor College of Medicine, members of the TMC - Genomic Center for Infectious Disease (TMC-GCID) program (https://gcid.research.bcm.edu/overview) are leveraging existing infrastructure, together with an active and robust sample collection stream linked to both clinical and community testing, to characterize SARS-CoV-2 virulence and susceptibility across the region. This application requests supplemental funding to the TMC-GCID to help support SARS-CoV-2 community-wide surveillance, complete viral genome sequencing, nasopharyngeal microbiome profiling, and targeted host genetic analyses. The primary objective of this supplement will be achieved through the collaborative efforts of a multidisciplinary, integrated team of basic and physician scientists with a track-record of collaboration and who are already delivering on the primary goals of the TMC-GCID. The overall goals of our GCID supplement is to study the biology of SARS-CoV-2 infection, the host and microbial genetics associated with disease, and to address community needs, particularly in underserved communities, through the following aims: i) expand an operational Emergency Use Authorization- (EUA-) and IRB-compliant COVID-19 qPCR screening/surveillance program featuring online enrollment and consent as well as HIPAA-compliant return of results, ii) sequence and analyze full-length SARS-CoV-2 genomes from infected individuals collected from the TMC and surrounding area, iii) identify microbial co-colonization/co-infections that predict COVID-19 disease severity and/or outcome, iv) Characterize the host genetic variation with respect to viral titer, disease severity, and outcome in patients positive for COVID-19, including polymorphisms in human leukocyte antigen (HLA), angiotensin-converting enzyme 2 (ACE2), and natural killer cell immunoglobulin-like receptor (KIR) regions. This supplement will leverage the cutting edge, high-throughput sequencing strategies and technologies supplied by the TMC-GCID Sequencing Technology (ST) Core, in generating discoveries, data, tools, and reagents that will be analyzed and disseminated to the infectious disease community through the TMC-GCID Data Management Analysis and Resource Dissemination (DMARD) Core. The result will be a comprehensive genetic profiling of hosts and microbes in SARS-CoV-2 infection that will reveal pathogen genetic variants associated with individual host response phenotypes that will inform precision medicine-based therapeutics and diagnostics, not just for SARS-CoV-2, but for other pandemic threats that we have already observed to profoundly change the world around us.