Pseudomonas aeruginosa in catheter-associated urinary tract infections: determining virulence factors in a murine model

Abstract

Hospitalized patients with indwelling catheters face a daily risk of developing catheter-associated urinary tract infection (CAUTI). Catheters provide a point of entry and a surface for bacterial colonization, which can manifest either as asymptomatic bacteriuria or symptomatic infection. However, the relationship and timing of these outcomes is unclear. In this study, we leveraged Pseudomonas aeruginosa, an opportunistic pathogen among the leading causes of CAUTI, unique in that it is not associated with the normal human microbiome. In chapter two, using an outbred murine CAUTI model with the strain PA14, we identified two distinct infection outcomes: acute infection, with host morbidity and mortality within the first week, and chronic infection, with asymptomatic colonization in the second week. These outcomes were found to be driven by distinct mechanisms. For acute infections, the type III secretion system (T3SS) was indispensable. Bacterial mutants lacking a functional T3SS, injection pore, T3SS effector proteins, or T3SS transcriptional activation did not cause acute infection, but retained the ability to chronically colonize the urinary tract at levels similar to the wild-type strain. Consistently, through overexpression of the T3SS positive master regulator ExsA, all mice had acute infection. These data suggest that colonization and symptomatic activity are independent processes. In chapter three, we examined how the urinary environment shapes P. aeruginosa behavior, focusing on the Entner-Doudoroff (E-D) metabolic pathway, which is induced by urea in urine and is the only glucose metabolism pathway in this species. The deletion mutants lacking the essential E-D pathway genes eda and edd were dispensable in vivo, showing no difference in host survival or bacterial colonization compared to the wild-type stain. In contrast, deletion mutants of the non-essential E-D pathway genes zwf and pgl showed minor fitness defects, including reduced catheter and kidney colonization and increased host survival. Together, these studies highlight the complexity of P. aeruginosa CAUTI, revealing that asymptomatic colonization and symptomatic infection are distinct processes shaped by specific virulence factors and metabolic responses to the urinary environment. These findings provide a basis for developing targeted therapeutics that differentiate between colonization and infection in catheterized patients.