Host-microbe interactions and SARS-CoV-2 susceptibility and symptoms in a novel human challenge model

摘要 据报道，新冠肺炎的病原体SARS-CoV-2已导致6亿多人死亡 全球感染人数和650万人死亡。尽管有几种抗病毒药物、单抗和 尽管免疫调节治疗改善了患者的预后，但新冠肺炎的死亡率仍然高得令人无法接受。 此外，尽管采取了缓解措施，并开发了几种高效疫苗，但SARS-CoV-2 继续在全球传播，几乎可以肯定该病毒将成为人类人口的地方性流行病。 因此，迫切需要确定改变SARS-CoV-2易感性和严重性的宿主因素 指导感染预防策略，并为未来的疫苗和治疗开发研究提供信息。非典-- CoV-2人类挑战实验为研究这些宿主因素提供了前所未有的机会 标准化病毒接种、病毒暴露的准确时间和环境条件，从而 控制不可避免地混淆自然感染研究的因素。这项提议的总体目标是 确定上呼吸道微生物组特征和宿主基因表达谱，以改变易感性 以及SARS-CoV-2感染的症状。这项研究将利用之前收集的临床数据和 在没有血清学的健康成年人中进行的首例人类SARS-CoV-2挑战研究的样本 以前感染或接种过疫苗的证据。我们将进行连续的鸟枪式元基因组和RNA测序 采集了34名接种了SARS-CoV的成年人的中鼻甲样本。 2/人/GBR/484861/2020年)，其中18人(53%)出现聚合酶链式反应确认感染。在目标1中，我们将使用鼻音 在基线和接种病毒后立即(-1至+3天)收集样本以鉴定微生物组 与抵抗SARS-CoV-2感染相关的特征和宿主转录反应。在目标2中，我们 将使用在-1天至+14天期间收集的鼻样来表征上呼吸道的变化 SARS-CoV-2感染过程中发生的微生物组和宿主转录组及其相关的微生物组和 转录组图谱与SARS-CoV-2感染特定症状的存在和严重程度。在这两个地方 目标，我们将使用创新的多组学分析来确定患者特征、上层 呼吸道微生物组-转录组图谱，以及SARS-CoV-2易感性和症状。这项研究将 鉴定与SARS-CoV-2易感性和症状相关的上呼吸道细菌种类 并可能导致合理设计的益生菌的开发，以防止SARS-CoV-2感染。 此外，对SARS后在上呼吸道发生的宿主反应的详细了解- CoV-2的暴露和感染可以为鼻用疫苗的开发提供信息，并为宿主识别新的靶点。 定向诊断或治疗学。最后，整合微生物组和宿主转录组数据的分析将 阐明上呼吸道微生物区系和宿主免疫系统相互作用影响的机制 对SARS-CoV-2和其他呼吸道病毒引起的感染的易感性和严重性。

ABSTRACT SARS-CoV-2, the etiological agent of COVID-19, has been responsible for more than 600 million reported infections and 6.5 million deaths globally. Although several antivirals, monoclonal antibodies, and immunomodulatory treatments improve patient outcomes, mortality from COVID-19 remains unacceptably high. Moreover, despite mitigation measures and development of several highly effective vaccines, SARS-CoV-2 has continued to spread globally, making it almost certain that the virus will become endemic in human populations. There is therefore a critical need to identify host factors that modify SARS-CoV-2 susceptibility and severity to guide infection prevention strategies and inform future vaccine and therapeutic development studies. SARS- CoV-2 human challenge experiments provide an unprecedented opportunity to study these host factors by standardizing the viral inoculum, the precise timing of viral exposure, and environmental conditions, thereby controlling for factors that inevitably confound natural infection studies. The overall objective of this proposal is to identify upper respiratory microbiome features and host gene expression profiles that modify susceptibility to and symptoms of SARS-CoV-2 infection. This research will leverage previously collected clinical data and samples from a first-in-human SARS-CoV-2 challenge study conducted in healthy adults without serological evidence of prior infection or vaccination. We will perform shotgun metagenomic and RNA sequencing of serially collected mid-turbinate nasal samples from 34 adults who were inoculated with a wild-type virus (SARS-CoV- 2/human/GBR/484861/2020), 18 (53%) of whom developed PCR-confirmed infection. In Aim 1, we will use nasal samples collected at baseline and immediately following viral inoculation (days -1 to +3) to identify microbiome features and host transcriptional responses associated with resistance to SARS-CoV-2 infection. In Aim 2, we will use nasal samples collected between days -1 and +14 to characterize changes in the upper respiratory microbiome and host transcriptome that occur during SARS-CoV-2 infection and correlate microbiome and transcriptome profiles with the presence and severity of specific symptoms of SARS-CoV-2 infection. In both Aims, we will use innovative multi-omics analyses to identify relationships between patient characteristics, upper respiratory microbiome-transcriptome profiles, and SARS-CoV-2 susceptibility and symptoms. This research will identify upper respiratory bacterial species associated with susceptibility to and symptoms of SARS-CoV-2 infection and could lead to development of rationally designed probiotics that prevent SARS-CoV-2 infection. Further, a detailed understanding of the host responses that occur in the upper respiratory tract following SARS- CoV-2 exposure and infection could inform development of nasal vaccines and identify novel targets for host- directed diagnostics or therapeutics. Finally, analyses integrating microbiome and host transcriptome data will elucidate mechanisms by which the upper respiratory microbiota and host immune system interact to influence susceptibility to and severity of infections caused by SARS-CoV-2 and other respiratory viruses.