Influence of the nasal microbiome on host susceptibility and response to respiratory viruses

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PROJECT SUMMARY The nasal cavity has a unique microbiome, which is expected to significantly affect local immune response and in turn, susceptibility of the host to respiratory viruses. However, we know little about these potential host- microbe interactions. Our long-term goal is to elucidate how microbiome-immune interactions and dynamics within the nasal cavity affect host susceptibility to infectious and inflammatory conditions. This project’s objective is to determine natural dynamics of correlations between nasal microbiome and local immune environment and how this relationship affects host susceptibility to respiratory viral infections. Our central hypothesis is that during homeostasis, the nasal microbiome impacts local antiviral immune defenses, including epithelial integrity, mucus properties, and antiviral cytokines and specific nasal microbiome-immune environments defined by low-inflammation and high-interferon levels will confer greater natural protection against respiratory viral infections. The rationale for this project is that our knowledge regarding the adult nasal microbiome and immune environment during homeostasis is limited. Addressing this gap can immediately improve our fundamental understanding of the adult nasal cavity and inform strategies that promote naturally occurring protection against respiratory viral infections. Aim 1. Elucidate dynamics of the homeostatic nasal microbiome and immune environment in adults. We will achieve this aim by studying (i) the homeostatic nasal microbiome and innate immune profile in a cross-section of adults (n = 400) and (ii) assessing short- and long-term dynamics of adult nasal environment by selecting and following 118 adults through monthly and quarterly dense sampling over a 12-month period. Aim 2. Determine how the nasal microbiome-immune environment affects susceptibility to an intra- nasal virus challenge. We will achieve this aim by studying how pre-vaccination nasal microbiome-immune environments impact post-vaccination viral infection and replication among adult FluMist® recipients (n = 200) per year in Years 1 and 2. Aim 3. Elucidate interactions between nasal microbiome, nasal immune environment, and host susceptibility to respiratory viruses in vitro. We will achieve this aim by assessing effect of nasal microbiome composition and nasal bacterial absolute abundance on: (i) innate immune defenses and (ii) influenza A, rhinovirus, and SARS-CoV-2 infectivity using an innovative in vitro nasal microbiome-respiratory epithelial co-culture model. The proposed research is innovative because it represents a departure from the status quo by assessing how the nasal microbiome, which is ubiquitous and diverse, could affect natural immune environment. significant because it is expected to identify nasal microbiome features and immune profiles that confer natural antiviral protection, which could inform novel strategies to reduce the risk for respiratory viral infections.