Host-Microbe Interactions and SARS-CoV-2 Susceptibility and Symptoms in aNovel Human Challenge Model - 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.
