Decoding influenza-induced damage: what's all the HYP(oxia) about?

The National Heart, Lung, and Blood Institute awarded ST Jude Children's Research Hospital Inc. $150,104 on March 4, 2026, under the Cardiovascular Diseases Research program (CFDA 93.837) to investigate influenza-induced lung damage and hypoxemia.

The research project, "Decoding Influenza-Induced Damage: What's All the Hyp(oxia) About?," uses damage-responsive fibroblasts (DRFibs) and ADAMTS4-knockout mice to elucidate how preventing T cell and fibroblast communication affects T cell phenotype, clonality, and specificity. The work employs spatial transcriptomic, single-cell RNA sequencing, and T cell receptor sequencing approaches. The project addresses pathogenic signals that promote damage-associated niches in the lung, particularly the role of ADAMTS4-produced versican degradation in influenza-induced mortality and hypoxemia, a key predictor of poor outcomes in influenza and pneumonia severity scores.

Performance occurs in Memphis, Tennessee, with a period of performance ending November 30, 2028. The funding is classified as a Project Grant.

Abstract

Influenza viruses cause seasonal and epidemic outbreaks that pose a recurring burden on global public health systems. Despite annual vaccination efforts, severe influenza virus infections occur each year and disproportionally impact children, the elderly, and those with pre-existing conditions. Influenza-induced lung damage and persistent inflammation are highly variable across infected individuals, with limited understanding of the pathogenic signals that contribute to these processes. This proposal hopes to shed light on the pathogenic signals that promote the development of damage-associated niches in the lung leading to more severe disease outcomes. Prior members of the thomas laboratory discovered a subset of damage- responsive fibroblasts (drfibs) that reside in damage-associated lung niches and uniquely contribute to influenza-induced lung damage. Drfibs produce high levels of ADAMTS4, an enzyme that degrades versican, an extracellular matrix component produced in the lung during development and infection. Interestingly, when mice lack ADAMTS4, they are protected from influenza-induced mortality compared to wildtype littermate controls. IT was found that a dense versican barrier prevented CD8 t cell: drfib crosstalk, leading to fewer ifng-producing CD8 t cells, less lung damage, and improved hypoxemia in ADAMTS4 KO mice. This proposal seeks to exploit ADAMTS4 KO mice as a model of damage-associated niche disruption to elucidate how preventing t cell: drfib communication affects t cell phenotype, clonality, and specificity using spatial transcriptomic, scrnaseq, and TCR sequencing approaches. Low blood oxygen saturation (hypoxemia) is included as a predictor of poor outcomes in 9 out of 12 influenza and pneumonia severity scores, highlighting a strong correlation between impaired oxygenation and influenza severity. Tissue-level hypoxia in the lungs is also a characteristic of influenza illness. Previous research has shown that a cell's microenvironment can significantly impact its phenotype; however, the impact of hypoxia on immune and stromal cell subsets in the lungs during and following a respiratory virus infection has not yet been explored. This F32 proposal will employ a unique mouse model to reveal how hypoxia in the lung microenvironment during severe respiratory viral infection influences the phenotypes of t cells and fibroblasts. Successful completion of the proposed will generate a unique atlas of hypoxic cell phenotypes that could have broad implications for the field as many severe respiratory viruses induce hypoxemia and lung damage. DR. Paul g. Thomas, a well-established influenza immunologist and member of the center of excellence for influenza research and response, and ST. Jude children's research hospital will be integral to achieving the goals outlined in this proposal by providing technical training, practice in scientific communication, mentorship experience, on-site access to state of the art resources, and networking opportunities with influenza experts. Completion of the research and training goals outlined in this F32 proposal will unveil novel mechanisms of influenza pathogenesis while supporting the development of the applicant's independent research career.