Single-Cell Biology of Respiratory Viral Infections in the Nasal Mucosa

Abstract

Respiratory viral infections are a major cause of morbidity across the lifespan, yet the cellular programs that coordinate antiviral immunity in the human nasal mucosa remain incompletely defined. This thesis uses single-cell RNA sequencing to characterize epithelial and immune responses to respiratory viruses directly at the site of infection, with a focus on how viral identity, host age, and immune history shape mucosal immunity and clinical outcomes. In adults with SARS-CoV-2 infection, we profiled nasopharyngeal samples collected across multiple pandemic waves to define shared and variant-specific epithelial and immune cell states and to determine how these responses relate to disease severity and prior vaccination. These analyses reveal that infected epithelial cells adopt conserved activation programs across viral variants, while variant-specific cellular states correlate with disease severity. Prior vaccination is associated with altered myeloid responses within the nasal mucosa, suggesting that systemic immune memory can reshape tissue-level responses during breakthrough infection. To define virus-specific immune responses in early life, we generated a large single-cell atlas of the pediatric nasal mucosa from children infected with SARS-CoV-2, rhinovirus, or respiratory syncytial virus, alongside uninfected controls. Comparative analyses identify distinct epithelial differentiation programs and immune activation patterns associated with each virus, linking viral tropism and epithelial state to divergent clinical phenotypes including wheezing and severe bronchiolitis. Together, this work establishes a single-cell framework for understanding how the human nasal mucosa coordinates antiviral defense across age groups and respiratory pathogens. By defining epithelial and immune cell states at the primary site of infection, these studies offer cellular insights relevant to disease severity, vaccine responses, and susceptibility to respiratory illness.