Integrated Metagenomic and Metatranscriptomic Characterization of Inflammatory Chronic Rhinosinusitis Endotypes

摘要 SARS-CoV-2大流行要求迅速做出反应，以解决广泛的医疗和科学问题 减少对人口的伤害，减缓并最终消除疫情的问题。要了解 将导致有效治疗和疫苗的病程、病史和发病机制至关重要 纵向上的几个基本科学问题：病毒、遗传、生态因素和共病/共病 感染的危险因素需要1)有症状和无症状的感染；2)延长 脱落；3)急慢性后遗症。特别是，我们必须定义减少病毒载量的相关因素 在疾病早期的上呼吸道，以及后来定义严重下呼吸道的宿主病毒反应 以细胞因子风暴为前奏的呼吸系统疾病和ARDS。我们假设是一组 病毒(高病毒载量、毒力的特定病毒特征、呼吸道病毒混合感染和病毒群)、生态 (如微生物群落结构/功能)和宿主(局部粘膜免疫反应)因素将 预测疾病结果和严重程度。以下是我们的具体目标，以解决我们的假设：目标1： 确定SARS-CoV2病毒载量的纵向动力学，以建立鼻部病毒载量与 病毒的脱落与疾病的严重性有关。目的2：描述SARS-CoV2感染如何改变鼻腔 新冠肺炎期间微生物群组成、结构与继发细菌感染。目标3：检查是否 SARS-CoV2感染期间鼻微生物组模式与局部免疫反应和 细胞因子风暴。总的来说，这项研究将确定SARS-CoV2病毒动力学、持久性、 病毒-宿主和微生物组的相互作用。具体地说，我们的建议将增进我们对 新冠肺炎患者上呼吸道微生物群及其在局部免疫应答规划中的作用 SARS-CoV2感染及其对新冠肺炎预后的影响。

SUMMARY The SARS-CoV-2 pandemic demands a swift response to address a broad range of medical and scientific questions to mitigate harm to populations and slow and eventually eliminate the epidemic. To understand the course, history, and pathogenesis that will lead to effective therapies and vaccines it is critical to answer several fundamental scientific questions longitudinally: Viral, genetic, ecological factors and co-morbidity/co- infections risk factors need to be identified for 1) symptomatic and asymptomatic infection; 2) prolonged shedding; and 3) acute and chronic sequelae. In particular we must define correlates of reduced viral load in upper airways early in disease, and the host-viral response that defines later severe lower respiratory disease and ARDS that is prefaced by cytokine storm. We hypothesize that a combination of viral (high viral load, specific viral signature of virulence, respiratory viral co-infection and virome), ecological (such as, microbiome community structure/function) and host (local mucosal immune response) factors will predict disease outcomes and severity. Below are our specific aims to address our hypothesis: Aim 1: Determine longitudinal kinetics of SARS-CoV2 viral load to establish association between nasal viral load and viral shedding with disease severity. Aim 2: Characterize how SARS-CoV2 infection changes nasal microbiome composition, structure and secondary bacterial infection during Covid-19. Aim 3: To examine if nasal microbiome patterns during SARS-CoV2 infection are associated with local immune responses and cytokine storm. Collectively, this study will identify determinants of SARS-CoV2 viral kinetics, persistence, virus-host and microbiome interactions. Specifically, our proposal will advance our understanding of the role of the upper airway microbiome in Covid-19 and establish its role in programming of the local immune response upon SARS-CoV2 infection and effects on Covid-19 outcomes.