Intriguingly, a UPEC factor that reduces inflammasome activation has also been described. Several bacterial toxins such as nigericin ( Streptomyces hygroscopicus), valinomycin (several Streptomyces species), maitotoxin ( Gambierdiscus toxicus), aerolysin ( Aeromonas hydrophila) and listeriolysin O ( Listeria monocytogenes) activate the NLRP3 inflammasome. Activated caspase-1 cleaves the pro-inflammatory cytokines pro-IL-1β and pro-IL-18 enabling their release from cells, and also processes gasdermin D to enable pyroptotic cell death. Upon activation, NLRP3 oligomerizes in the presence of the adaptor protein apoptosis-associated speck-like protein containing a CARD (ASC) and the effector caspase-1, resulting in auto-proteolysis and activation of caspase-1. NLRP3, which is the best-characterized inflammasome-forming pattern recognition receptor, is activated by a wide array of host-derived and exogenous ligands, including microbial toxins. They comprise a danger-sensor pattern recognition receptor, such as an NLR family member, as well as downstream signalling components. Inflammasomes are large cytosolic multiprotein complexes that are activated by infection and/or cellular stress.

UPEC strains that kill macrophages also trigger activation of the nod-like-receptor pyrin domain-containing 3 (NLRP3) inflammasome. Since macrophages play an essential role in the recruitment of host-protective neutrophils during experimental UTI, UPEC-mediated killing of macrophages may provide an additional mechanism by which this pathogen can evade neutrophil responses. We recently demonstrated that CFT073, a virulent blood culture isolate recovered from a patient with pyelonephritis, triggers rapid cell death in both human and mouse macrophages.

For example, the UPEC periplasmic protein YbcL inhibits transepithelial neutrophil migration in in vitro and in vivo models of murine cystitis. The capacity of UPEC to downregulate a range of inflammation-related genes may contribute to the dampening of neutrophil recruitment to the site of infection. Although host-protective pro-inflammatory mediators such as IL-6 and IL-8 are released during active UTIs, several studies have also demonstrated that UPEC can actively suppress such responses. The innate immune system is composed of both soluble factors and cellular mediators that provide a coordinated response to enable UPEC detection and destruction. It is therefore crucial that we improve our current understanding of UPEC pathogenesis in order to develop novel strategies to prevent and/or treat these infections. Although antibiotics are routinely used to treat UTIs, the emergence of multidrug-resistant UPEC strains poses a significant challenge to effective treatment of such infections. The majority of acute and chronic UTIs are caused by uropathogenic E. Infection of the bladder (cystitis) can lead to kidney infection (pyelonephritis), associated renal damage and life-threatening sepsis. Urinary tract infections (UTIs) are one of the most common bacterial infections, and can be associated with serious complications. Together, our findings reveal that Cof fine-tunes production of hemolysin, an important determinant of both UPEC-mediated inflammasome activation and human macrophage cell death. Random transposon mutagenesis also identified the cof gene, which encodes a poorly characterized phosphatase, as a novel hemolysin regulator a CFT073 mutant deleted for the cof gene secreted significantly reduced levels of HlyA, had diminished hemolytic activity, and was impaired in its capacity to trigger human macrophage cell death and IL-1β release. Our approach revealed that the hemolysin A (HlyA) toxin is essential for triggering both cell death and NLRP3 inflammasome-mediated IL-1β release in human macrophages. In this study, we used random transposon mutagenesis in the reference strain CFT073 to identify UPEC genes that mediate human macrophage cell death. We recently showed that some UPEC strains rapidly kill human macrophages via an NLRP3-independent pathway, and also trigger NLRP3-dependent IL-1β processing. UPEC uses numerous mechanisms to subvert the innate immune system, including targeting macrophage functions.

coli (UPEC) causes the majority of urinary tract infections (UTIs), which are a major global public health concern.

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