Defining the Role of Aerobic Respiration in Uropathogenic Escherichia coli Physiology and Pathogenesis

Abstract

Uropathogenic Escherichia coli (UPEC) is the leading cause of urinary tract infections and among the most successful human bacterial pathogens worldwide. Despite being a facultative anaerobe, UPEC requires aerobic respiration to support biofilm formation and pathogenesis in the urinary tract. Although the need for aerobic respiration is well-established, the mechanisms underlying this requirement remain unclear. In this work, I define the contribution of aerobic respiration to UPEC physiology and pathogenesis in the urinary tract. I determine that UPEC heterogeneously expresses respiratory complexes across niches and modes of growth, and that this respiratory heterogeneity provides a fitness advantage to UPEC during bladder infection. Through a systematic investigation of aerobic respiratory quinol oxidases, I identify the high affinity respiratory oxidase cytochrome bd as a key regulator of UPEC biofilm formation and pathogenesis in the bladder. Loss of cytochrome bd disrupts the production and spatial organization of the protective biofilm extracellular matrix, consequently increasing biofilm susceptibility to clinically relevant antibiotics. Additionally, I determine that cytochrome bd mediated respiration supports UPEC pathogenesis in the bladder by enhancing the ability for UPEC to intracellularly infect urothelial cells. Intracellular bacterial respiration mediated by cytochrome bd depletes cytosolic oxygen, rewires host cell metabolism, antagonizes apoptosis, and preserves the replicative niche used by UPEC to avoid antibiotics and immune defenses in the bladder. Collectively, this work defines the role of aerobic respiration in urinary tract infection pathogenesis, reveals the multifaceted role of cytochrome bd in UPEC physiology, and identifies cytochrome bd as a promising target for the development of antimicrobial agents that rewire bacterial metabolism to subvert bacterial pathogenesis in the urinary tract.