Microbial Dysbiosis in Chronic Lung Allograft Dysfunction

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PROJECT SUMMARY: Lung transplant is the only curative treatment for end stage lung diseases such as idiopathic pulmonary fibrosis, COPD, cystic fibrosis and pulmonary hypertension. However, long-term survival of lung transplant recipients (LTRs) is the lowest among all organ transplantations with a median survival of 6 years. Approximately 50% of LTR’s develop chronic rejection within 5 years post-transplantation, a syndrome referred to as chronic lung allograft dysfunction (CLAD). CLAD pathogenesis is poorly understood. We and others have shown that lung dysbiosis (disruption of microbiota homeostasis) is strongly associated with CLAD, although to date it is unclear if dysbiosis is the cause or effect of CLAD. Unlike, gut dysbiosis which is an established risk for chronic inflammatory diseases; the role of lung dysbiosis and the mechanisms linking it to CLAD remain to be determined, representing a critical knowledge gap. Our objectives are to use a longitudinal approach to define the pathogenic lung microbiome that predates CLAD onset and investigate mechanisms for microbiome-induced fibrogenesis that increase CLAD susceptibility. Our hypothesis is that lung dysbiosis inhibits epithelial autophagic clearance of pro-fibrotic cytokines in an IL-33 dependent manner, thereby augmenting fibrogenesis and risk for CLAD. SA1: To investigate the role of IL-33 blockade in attenuation of lung dysbiosis related fibrogenesis and CLAD in a murine lung transplant model. SA2: To elucidate the mechanisms of IL-33 regulation of autophagy that are linked to pro-fibrotic responses in the lung. SA3: To determine the relationship between human lung dysbiosis, IL-33 and CLAD susceptibility. Completion of the proposed studies will (a) define the mechanistic link between airway microbial dysbiosis in lung transplant recipients to dysregulated epithelial responses and CLAD; (b) provide proof-of-concept that IL-33 blockade can favorably modulate microbiome mediated pro-fibrotic response leading to CLAD. (c) Identify specific airway microbiome signatures that identify those at risk for CLAD.