Aryl polyenes expressed by Uropathogenic Escherichia colicontribute to pathogenesis in a mouse model with an aberrant macrophage polarization

Abstract

Abstract Uropathogenic Escherichia coli (UPEC) is a causative agent of urinary tract infections (UTIs), and one of the most common causes of pyelonephritis. Interestingly, UPEC is often found as a non-pathobiont in the gut flora. The transition from gut flora to pathogen for UPEC is dependent upon a flexible tropism, and a number of virulence factors that aid in UPEC’s colonization and invasion of the urinary tract. We recently demonstrated a role for the E. coli aryl polyenes (APEs) as a potential UPEC fitness factor. The current hypothesis is that APEs contribute to UPEC virulence in the host system. APEs are encoded by a biosynthetic gene cluster (BGC) family identified among many gram-negative bacteria. The products of this BGC family are lipids comprised of an aryl head group and conjugated double bond system, which are structurally reminiscent of established virulence factors found in gram-positives. In addition to the structural mimicry, UPEC APE expression conferred resistance to reactive oxygen species and enhanced biofilm formation. In a UTI mouse model, infection with UPEC that constitutively expressed APEs (UPEC APE+) increased pathogenicity. Transcriptomic analyses of in vitro co-incubation experiments indicates that UPEC APE+exposure influences the macrophage gene transcription profile differently as compared to UPEC WT. Taken together, our findings suggest that APE expression aids in bacterial virulence and immune modulation during infection. Therefore, targeting the biosynthetic gene product APE may be a viable therapeutic approach to reduce fitness of pathogenic populations while leaving commensal gut microflora unharmed and minimize tissue damage. NIAID RO1AI153173 Cleveland Clinic Foundation