Role of Wnt/β-catenin pathway in alveolar epithelial repair during tuberculosis and its regulation by chronic type I interferon signaling

About This Grant

Project Summary Tuberculosis (TB) remains a leading cause of mortality worldwide, with lung damage being a key driver of disease severity and poor outcomes. Alveolar epithelial cells are critical for maintaining lung homeostasis and promoting repair, processes that are tightly regulated by Wnt/β-catenin signaling. Our preliminary data indicate that Mycobacterium tuberculosis (Mtb)-induced inflammation disrupts alveolar epithelial integrity in TB-susceptible mice, leading to impaired surfactant production and defective lung regeneration. Strikingly, this is associated with a significant reduction in β-catenin levels. Notably, inhibition of type I interferon (IFN-I) signaling restores β-catenin expression, suggesting a previously unrecognized role of IFN-I in suppressing Wnt/β-catenin activity and alveolar repair. We aim to investigate how chronic IFN-I signaling impairs Wnt/β-catenin function, leading to defective epithelial repair and exacerbated lung pathology in TB. Specifically, in aim1, we will define the role of Wnt/β-catenin in alveolar epithelial repair following Mtb infection. We will assess how Wnt/β-catenin activation or inhibition influences alveolar type 2 (AT2) cell proliferation, differentiation, and stemness using murine and human primary alveolar cells. Additionally, we will evaluate lung histopathology, epithelial marker expression, and AT2 cell differentiation in TB-resistant and susceptible mice. In aim2, we will determine how IFN-I signaling suppresses Wnt/β-catenin activity during TB-induced lung damage. Using genetic and pharmacological approaches, we will investigate the molecular mechanisms by which IFN-I signaling modulates Wnt/β-catenin function and identify key mediators of IFN-I–Wnt/β-catenin crosstalk as potential therapeutic targets. Finally, in the aim3 we will evaluate the therapeutic potential of targeting Wnt/β-catenin and IFN-I pathways to enhance alveolar repair. We will test Wnt/β-catenin activators, such as GSK3β and Porcupine inhibitors, as well as IFN-I blockade using anti-IFNAR antibodies in murine TB models. Therapeutic efficacy will be assessed through histopathological analysis, epithelial barrier integrity, inflammatory responses, and bacterial burden. This study will provide novel insights into the interplay between IFN-I signaling and Wnt/β-catenin in TB pathogenesis, uncovering mechanisms that impair alveolar repair. By identifying host-directed therapeutic strategies, we aim to enhance lung recovery and improve outcomes for TB patients.