Establishing lifelong trajectories of pulmonary health

PROJECT SUMMARY: Carefully calibrated responses of lung resident leukocytes and lung epithelial cells are essential to meet the conflicting demands of protecting critical gas exchange surfaces from pathogens (resistance) while preventing unrestrained inflammation and promoting repair (resilience). The overall premise of this application is that lung resistance and resilience pathways are remodeled by neonatal colonization by commensal microbiota, contributing to poor lung health and chronic respiratory disease beyond infancy. Infancy represents a critical ontogenic window when evolving microbial communities colonizing the infant potentially program lung homeostasis. This paradigm is exemplified by epidemiological observations linking perturbations in the microbiota (dysbiosis) due to antibiotics (ABX), a regrettably common occurrence in pediatric clinics, is associated with increased severity of viral respiratory tract infection (RTI), increased need for hospital admissions, and the development of chronic inflammatory diseases that commence during infancy, reemphasizing the need for novel therapies to support this vulnerable population. Published and preliminary data from my laboratory show that disruption of commensal colonization during the perinatal window disrupts the accrual, functional competence, and long-term fate of lung resident leukocytes and interrupts the epithelial cell differentiation program. Fecal transfer can correct some of these deficits and improve clinical outcomes in murine and primate models. Nevertheless, a unifying framework explaining how early-life dysbiosis remodels the developmental program in the tissue-resident lymphocyte-epithelial cell homeostatic unit remains unresolved2. Knowledge of specific taxa essential for lung homeostasis and the critical window during which this microbiota program the lung homeostatic pathways remain undefined. Addressing these essential gaps of knowledge is a key objective of the proposed R35 program. This application explores the concept that dysbiosis interrupts the accrual and long-term fate of lung-resident CD8+ T cells [Theme 1: Resistance] and reprograms the regenerative pathways in the alveolar epithelial cells [Theme 2: Resilience]. We will explore the therapeutic potential of specific microbiota to mitigate these deficits and decrease severe LRTI during infancy [Theme 3: Remediation].