Lysine Decarboxylation aids in UPEC intracellular survival in the early stages of urinary tract infection

Abstract

Acid stress is a substantial challenge to bacterial life. Acidic conditions can damage the bacterial cell envelope and disturb vital physiological processes, such as enzymatic activity, protein folding, membrane- and DNA maintenance. Escherichia coli occupies numerous environmental and host niches with varying pH. Consequently, E. coli strains are equipped with multiple acid resistance (AR) mechanisms to withstand acidic conditions. Uropathogenic E. coli (UPEC), which accounts for >75% of urinary tract infections (UTIs) persist for years in the host, colonizing the gut and the vagina asymptomatically for long periods of time, while causing acute or chronic infection in the bladder. While these host niches have variable pH, no studies elucidated which AR mechanisms are used by UPEC during infection. Here, we generated a comprehensive list of AR deletion mutants and evaluated them in the acute stage of infection. We show that at the acute infection stage, mutants that lack cadA (AR4) are significantly attenuated. We go on to show that AR4 is specifically induced early during intracellular infection within urothelial cells. Deletion of cadA leads to fewer intracellular bacteria both in vitro and in the murine infection model. Treatment with bafilomycin, which blocks vacuole acidification rescues the cadA deletion phenotype intracellularly, suggesting that AR4 is important for UPEC survival inside the lysosome. Combined, this work begins to elucidate the specific contribution of each AR to UPEC pathogenesis.