Rare airway cell function in post-viral chronic inflammation - the airway epithelium serves as a barrier between the aerosol environment and the underlying submucosa

The National Institutes of Health National Heart, Lung, and Blood Institute awarded National Jewish Health $249,000 on July 24, 2026, under the Cardiovascular Diseases Research program (CFDA 93.837) to investigate rare airway cell function in post-viral chronic inflammation.

The research examines the role of microfold (M) cells in the post-influenza lung, particularly their contribution to secondary bacterial infection susceptibility and host protection. Using single-nucleus transcriptomic and epigenomic sequencing, the investigator will define M cell interactions with secondary bacterial pathogens and their regulation of lung mucosal immune responses. A secondary research objective addresses distal lung bronchiolization following severe influenza infection, focusing on basal-like cell expansion into the alveolar compartment and mechanisms regulating airway progenitor plasticity, including the role of SOX2 inactivation.

Performance occurs in Denver, Colorado. The project period runs from the award date through June 30, 2029. This is a Project Grant, the standard assistance type for NIH investigator-initiated research.

Inhaled air often carries noxious agents and pathogens that can injure the lung. Severe lung injury can lead to persistent inflammation, dysplastic repair, and permanent loss of gas exchange surface area. Airway cells contribute to regeneration following lung injury, although the heterogeneity of airway cell identity and specialized functions during lung repair is not well understood. My research centers on rare airway cell types and their function in the post-viral lung. My research in collaboration with others has studied the differentiation of an unexpected airway cell type, tuft cells, during repair. Using single nucleus transcriptomic and epigenomic sequencing to survey airway cells following influenza infection, I identified a rare airway cell present in the post-viral lung, microfold (M) cells. M cells are not well studied in the lung, but in other contexts associate with lymphoid follicles where they function in antigen sampling. The proposed R00 research will define the role of M cells in secondary bacterial infection. Much of the morbidity of pulmonary influenza infections can be attributed to secondary bacterial infection. Proposed experiments will determine if M cells increase susceptibility to secondary bacterial infection or if they function in host protection. Examining interactions between M cells and secondary bacterial infection will contribute to our understanding of lung mucosal immune regulation. A second outcome from my focus on airway repair following severe influenza infection is an effort to understand mechanisms regulating distal lung bronchiolization, a hallmark of multiple human lung diseases. After influenza infection, basal-like cells expand from the airway into the distal alveolar compartment. Airway inactivation of SOX2 leads to increased plasticity of airway progenitors during repair. The proposed R00 research will identify mechanisms downstream of SOX2 inactivation and determine the role of NKX2-1 in basal-like cells that expand in the distal alveolar compartment after influenza. The R00 research will be conducted at national jewish health, a leading institution in respiratory medicine with necessary resources and a collaborative scientific community.