Variation in hemolysin A expression between uropathogenic Escherichia coli isolates determines NLRP3-dependent vs. -independent macrophage cell death and host colonization

What is it about?

Uropathogenic E. coli (UPEC) is the major cause of urinary tract infections (UTI), one of the most common bacterial infections. Antibiotic resistance is becoming increasingly common in UPEC, as exemplified by the globally dominant E. coli sequence type 131 (ST131) clone. The innate immune system provides the first line of defense against invading microorganisms, and pathogens such as UPEC must employ sophisticated immune evasion strategies for successful colonization of the host. Knowledge of effective innate immune defense mechanisms against UPEC may ultimately guide the development of new non-antibiotic immune-directed therapies against this pathogen. Surprisingly little is known about interactions between UPEC and macrophages, innate immune cells with key roles in inflammation and host defense. In this study, we screened a panel of E. coli ST131 isolates for effects on human macrophage viability, finding that only those strains expressing the toxin α-hemolysin (HlyA) were cytotoxic. Through genetic deletion in an ST131 strain, we confirmed the essential role for this toxin in human macrophage cell death. We also observed considerable variation in the levels of HlyA expression between ST131 isolates, and importantly, we show that this variation profoundly influences the specific mechanisms by which macrophages die, as well as host colonization in a mouse UTI model. We find that low levels of HlyA enable host-protective responses, whereas high levels of HlyA disable innate immune responses and support host colonization. Our study thus identifies distinct and opposing roles for HlyA in both immune-mediated pathogen sensing and in pathogen-mediated immune evasion.

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