Evolutionary adaptation of pseudomonas aeruginosa in response to cftr modulator therapy in individuals with cystic fibrosis

The National Institute of Allergy and Infectious Diseases awarded Georgia TECH Research Corp $158,696 on November 19, 2026, under the Allergy and Infectious Diseases Research program (CFDA 93.855) to investigate the evolutionary adaptation of Pseudomonas aeruginosa in response to CFTR modulator therapy in individuals with cystic fibrosis.

The research characterizes genetic diversity of P. aeruginosa populations isolated from chronically infected patients on trikafta (elexacaftor/tezacaftor/ivacaftor) therapy and compares them to pre-treatment isolates, then assesses how trikafta influences pathoadaptive traits and antimicrobial resistance and tolerance in these populations. The work builds on a previously established biobank of P. aeruginosa isolates from four chronically infected individuals collected prior to trikafta initiation, with matched post-treatment sputum samples and 75 cultured and sequenced isolates per individual planned.

Work is performed at Atlanta, Georgia, with a period of performance from the award date through June 30, 2029. The project addresses a gap in understanding pathogen evolution under CFTR modulator therapy, as many patients with chronic P. aeruginosa infections do not completely clear the pathogen despite clinical improvements, and in some cases bacterial load increases after one year of therapy.

Abstract

Cystic fibrosis (CF) is a genetic disorder that results in thick mucus accumulation in the lungs, leading to chronic infections and progressive respiratory decline. Pseudomonas aeruginosa (PA) is an important pathogen in the CF lung, establishing chronic infections starting with a single infecting strain and evolving into diverse populations that lead to a deterioration of lung function. The advent of highly effective cftr modulator therapies (hemt), particularly elexacaftor/tezacaftor/ivacaftor (trikafta), has transformed clinical outcomes for people with CF (pwcf) by improving lung function and reducing bacterial load. However, many pwcf with chronic PA infections do not completely clear the pathogen despite clinical improvements, and in some cases, PA load increases after one year of therapy. The mechanisms by which PA adapts to this new lung environment remain poorly understood, representing a major GAP in our understanding of pathogen evolution under hemt-induced niche shifts. This proposal investigates the evolutionary dynamics of heterogeneous PA populations in response to trikafta treatment in pwcf with chronic lung infections. My overarching hypothesis is that modulator therapy drastically changes the niches available to PA in the lungs of pwcf leading to diverse pathoadaptive evolutionary strategies. To address this, i propose two aims: (1) characterize the genetic diversity of PA populations isolated from pwcf on trikafta and compare them to pre-treatment populations, and (2) assess how trikafta influences pathoadaptive traits and antimicrobial resistance and tolerance in these populations. I will build on a previously established biobank of PA isolates from four chronically infected individuals prior to starting trikafta, collect matched post-treatment sputum samples, and culture and sequence 75 isolates per individual. These isolates will be assessed for genomic diversity, presence of hypermutators, and resistance genes using short- and long- read sequencing platforms and bioinformatics pipelines. I will then evaluate antimicrobial susceptibility, aggregate formation, alginate production, motility, and cell surface hydrophobicity to characterize functional adaptations associated with treatment. The innovative approach of deep isolate-level analysis across matched timepoints enables insight into both within-host evolution and population-level heterogeneity. This project will also generate a valuable biobank of 300 post-trikafta PA isolates to complement the existing pre-treatment collection. Findings from this work will improve our understanding of persistent PA infections in the modulator ERA and provide insight into the evolutionary trajectory of PA in the modulator ERA. The research and training in this proposal will equip me with advanced skills in genomics, phenotypic analysis, and CF microbiology, supporting my long-term goal of becoming an independent investigator studying microbial evolution in chronic lung infections.