Investigating Relationships of the Upper Airway Microbiota with SARS-CoV-2 Susceptibility and Coronavirus Disease 2019 Disease Presentation

/ABSTRACT Coronavirus disease 2019 (COVID-19), caused by the SARS-CoV-2 virus, has had a worldwide impact with an estimation of over 775 million cases and seven million deaths. In 2020 and 2021, the United States saw a decline in life expectancy due to excess deaths due to COVID-19. Fortunately, the current era with effective vaccinations and therapeutic treatments has seen a reduction in overall disease severity and number of deaths due to COVID- 19. Despite these achievements, COVID-19 remains clinically unique with differential disease presentations. Some remain asymptomatic, others develop symptoms, require intubation, and some result in death in the most severe scenarios. However, due to changing variants, SARS-CoV-2 is likely to remain in circulation for the foreseeable future. Thus, the concern for adverse outcomes will continue to remain a public health threat. Although we already know factors that increase the risk for disease severity (i.e., age, underlying comorbidities, smoking), we must continue to improve our understanding of underlying factors that increase risk for susceptibility and symptoms. The microbiota has been linked to susceptibility and symptom manifestation for respiratory viruses such as influenza and respiratory syncytial virus. Therefore, since SARS-CoV-2 emerged, the microbiota has been a candidate predictor in the same sense for COVID-19. Despite numerous studies assessing COVID-19 and the upper respiratory microbiota, results have remained inconsistent. These studies are challenging due to confounding, which can bias results. We recognize many lifestyle factors influence the microbiota and, in most studies, these data are not collected to account for these biases. Additionally, most studies have been cross-sectional, which restricts their ability to understand temporality between the exposure and outcome (microbiota vs disease susceptibility and clinical presentation). The objective of this proposed work is to leverage data from a nationwide prospectively collected household transmission study to evaluate the relationship of the upper respiratory microbiota and SARS-CoV-2 susceptibility and COVID-19 disease presentation. Given SARS-CoV-2 exposed household members were tested daily and reported symptoms, I will use this unique data to evaluate whether characteristics of the upper airway microbiota prior to infection are associated with virus susceptibility and/or disease presentation (Aim I). I also will evaluate whether susceptibility of SARS-CoV-2 is associated with reductions in microbiota diversity and/or changes in bacterial abundance (Aim II). Lastly, I will investigate the generalizability of Aims I and II by using a second dataset that includes weekly testing and a longer follow-up period (Aim III). These aims intertwine to investigate this unclear relationship and will be the first in the field to include microbiota specimens prior to infection. Given the longitudinal nature of these data, I can address the temporality challenges encountered by previous studies (microbiota before infection). These results can indicate whether the upper respiratory microbiota should be considered a target for reducing SARS-CoV-2 risk and disease severity. 1 Project Number: 1F31AI191421-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Allergy and Infectious Diseases (NIAID) | Principal Investigator: Allison Chan | Institution: VANDERBILT UNIVERSITY, Nashville, TN | Award Amount: $34,934 | Activity Code: F31 | Study Section: Special Emphasis Panel[ZRG1 F18-E (20)] View on NIH RePORTER: https://reporter.nih.gov/project-details/1F31AI19142101A1