Uropathogenic Escherichia coli strain CFT073 disrupts NLRP3 inflammasome activation

Abstract

Successful bacterial pathogens produce an array of virulence factors that allow subversion of the immune system and persistence within the host. For example, uropathogenic Escherichia coli strains, such as CFT073, express Toll/IL-1 receptor-containing (TIR-containing) protein C (TcpC), which impairs TLR signaling, thereby suppressing innate immunity in the urinary tract and enhancing persistence in the kidneys. Here, we have reported that TcpC also reduces secretion of IL-1β by directly interacting with the NACHT leucin-rich repeat PYD protein 3 (NLRP3) inflammasome, which is crucial for recognition of pathogens within the cytosol. At a low MOI, IL-1β secretion was minimal in CFT073-infected macrophages; however, IL-1β release was markedly increased in macrophages infected with CFT073 lacking tcpC. Induction of IL-1β secretion by CFT073 and tcpC-deficient CFT073 required the NLRP3 inflammasome. TcpC attenuated activation of the NLRP3 inflammasome by binding both NLRP3 and caspase-1 and thereby preventing processing and activation of caspase-1. Moreover, in a murine urinary tract infection model, CFT073 infection rapidly induced expression of the NLRP3 inflammasome in the bladder mucosa; however, the presence of TcpC in WT CFT073 reduced IL-1β levels in the urine of infected mice. Together, these findings illustrate how uropathogenic E. coli use the multifunctional virulence factor TcpC to attenuate innate immune responses in the urinary tract.

Urinary Tract Infection: Pathogenesis and Outlook

“…Further, UPEC induces host expression of genes such as IDO , which, via generation of kynurenine metabolites, can cause decreased neutrophil migration across infected bladder epithelia, as evidenced from in vitro Transwell systems, as well as in mice [58, 59]. Some UPEC strains, such as CFT073, can also disrupt host signaling by producing TIR domain-containing proteins such as TcpC; this virulence factor interacts with the host adaptor MyD88 to disrupt TLR4 signaling, while also reducing urinary IL-1β in mice and inhibiting the NLRP3 inflammasome in macrophages [60, 61]. While robust innate defenses are able to repel most bacterial challenges, this inflammatory response may represent a double-edged sword.…”

Bladder resident macrophages: Mucosal sentinels

“…Inflammation is critical to induce recruitment of immune cells that subsequently kill uropathogens, and while macrophages are likely an important source of pro-inflammatory cytokines during UTI [52]. In addition to PRR activation, production of pro-inflammatory cytokines follows bacterial recognition through intracellular receptors such as inflammasomes [53,54]. For example, inflammasome activation leads to the release of proinflammatory mediators, such as IL-1β, and UPEC strains can induce the NLRP3 inflammasome in mouse models of UTI [54].…”

Regulation of mononuclear phagocyte function by the microbiota at mucosal sites

“…Macrophages are resident in the lamina propria of the bladder and notably express a variety of TLRs . Although interactions between the commensal microbiota and bladder macrophages have not been characterized, during UTIs bladder macrophages produce pro‐inflammatory cytokines following bacterial recognition by way of inflammasome activation . Resident macrophages in the bladder recruit Ly6C + cells (and neutrophils) to the bladder from the bloodstream during infection.…”