Essential Functions of Alveolar Epithelial Cells in Tuberculosis Pathogenesis

About This Grant

Abstract : Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), is a chronic bacterial infection. It remains a significant global health burden1, killing more than a million individuals annually. In 2025, there was a 15% rise in TB cases in the USA, with a major outbreak in Kansas and active TB cases in Maine. The current TB treatment options are limited, require months-long treatment regimens, and are largely ineffective against drug-resistant strains. Even after successful treatment, 40 to 60% of TB survivors suffer from TB-associated lung damage, causing chronic respiratory symptoms, long-term morbidity and mortality. However, currently there are no approved TB therapies that mitigate, prevent or reverse TB-associated lung damage, highlighting a major unmet clinical need. Alveolar epithelial destruction is a central feature of TB-associated lung damage, but the mechanisms driving this destruction remain poorly understood. Autopsy studies, animal models, and in vitro systems suggest that Mtb compromises the function of alveolar epithelium, leading to the loss of alveolar epithelial integrity. Our preliminary studies show that JHU083, a glutamine metabolism inhibitor, reduces lung bacillary burden in Mtb-infected mice and increases the expression of stemness markers by alveolar epithelial progenitor cells. Our central hypothesis is that Mtb infection compromises function of alveolar epithelial cells, resulting in the loss of both AT1 and AT2 cells, leading to epithelial destruction and lung damage. This project seeks to answer three fundamental questions: (1) Which alveolar epithelial cell functions are crucial for epithelial integrity in vivo? (2) What are the metabolic drivers of epithelial destruction in Mtb-infected lungs? (3) Can alveolar epithelial cells be metabolically reprogrammed to restore epithelial integrity in Mtb-infected lungs? Using a multidisciplinary approach—including single-cell transcriptomics, metabolomics, immunophenotyping, ex vivo co-culture systems and in vivo models of TB—will transform our understanding of TB pathogenesis by providing the first comprehensive in vivo dissection of the molecular and cellular drivers of alveolar epithelial destruction— a fundamental yet overlooked contributor to TB-associated lung damage and a major unmet clinical challenge. The successful completion of this work will transform our understanding of TB pathogenesis and catalyze host- directed strategies to mitigate, prevent or reverse lung damage in TB survivors.