RDP Pilot – Feder

CFF RDP Pilot

Evolutionary and mutational drivers of P. aeruginosa persistence through Trikafta

PI:  Alison Feder, PhD
Assistant Professor, Genome Sciences

Funding Period: 2022 – 2025

Abstract: Chronic Pseudomonas aeruginosa (Pa) lung infections are a major cause of morbidity and mortality in cystic fibrosis (CF) and have been intensively studied. Despite major advances (including the development of CFTR modulators), interventions which durably clear infection remain elusive, necessitating a more complete in vivo understanding of CF infection biology, specially during therapy. A key driver of intra-host natural history is the complex spatial architecture of the lung, which may contribute importantly to how these bacteria 1) initially colonize, spread and diversify within CF patients, and 2) persist when challenged by CFTR modulators. Unfortunately, pulmonary Pa is largely characterized from sputum, which obscures spatial dynamics. Here, we propose to exploit a new high-resolution genomic dataset of regional Pa from CF lungs before and after elexacaftor/tezacaftor/ivacaftor (ETI) treatment, and Bayesian phylogeographic methods not previously applied to intra-organ bacterial populations to reconstruct bacterial diversification and persistence through time and space with unprecedented detail by exploiting the genetic and spatial relationships among sampled isolates. In doing so, we will (1) quantify the spatial-temporal colonization history and movement of P. aeruginosa in the lungs of 9 people with CF before treatment with ETI, and (2) measure the impact of ETI treatment on P. aeruginosa migration and resilience, while determining if bacteria persist across multiple regions during ETI or if a spatially or genetically-restricted population persists and recolonizes the lung. The proposed research will yield a quantitative description of the colonization history, persistence behavior and migration patterns of Pa in CF lungs before and after ETI treatment, yielding novel insights on how chronic infections develop and persist. These measurements will enable future work that examines how regional infection and migration impacts clinical progression and treatment response.