Bringing down the host: enteropathogenic and enterohaemorrhagicEscherichia colieffector-mediated subversion of host innate immune pathways

Abstract

SummaryEnteric bacterial pathogens commonly use a type III secretion system (T3SS) to successfully infect intestinal epithelial cells and survive and proliferate in the host. Enteropathogenic and enterohaemorrhagic Escherichia coli (EPEC; EHEC) colonize the human intestinal mucosa, form characteristic histological lesions on the infected epithelium and require the T3SS for full virulence. T3SS effectors injected into host cells subvert cellular pathways to execute a variety of functions within infected host cells. The EPEC and EHEC effectors that subvert innate immune pathwaysspecifically those involved in phagocytosis, host cell survival, apoptotic cell death and inflammatory signalling -are all required to cause disease. These processes are reviewed within, with a focus on recent work that has provided insights into the functions and host cell targets of these effectors.

Modulation of the Inflammasome Signaling Pathway by Enteropathogenic and Enterohemorrhagic Escherichia coli

“…In the case of EPEC/EHEC, T3SS-dependent effectors have been demonstrated to modulate various immune signaling pathways (Santos and Finlay, 2015). In addition to the central role of NF-κB in many immune responses, NF-κB is also critical for the activation of the NLRP3-inflammasome because reduced NF-κB activity influences the transcription of NLRP3 and IL-1β (Figure 1; Bauernfeind et al, 2009; Qiao et al, 2012).…”

“…Specifically, EPEC/EHEC-mediated suppression of the NF-κB pathway and the mechanisms of those prominent NF-κB-suppressive effectors, such as NleB, NleC, NleE, NleH1, and Tir, have recently become clear and have been reviewed elsewhere (Santos and Finlay, 2015). In addition to the NF-κB pathway, an important role of cytosolic NLRs in the sensation of cellular distress caused by pathogens has been increasingly recognized (Moltke et al, 2013; Storek and Monack, 2015).…”

Immunomodulatory Yersinia outer proteins (Yops)–useful tools for bacteria and humans alike

“…1 These effector proteins affect nearly all areas of cellular life by modulating, inhibiting or even exploiting essential cellular mechanisms for the benefit of the microbe and in doing so might act in concert. [2][3][4] Furthermore, bacterial effector proteins might target more than one cellular signaling mechanism so that the currently known targets might not be comprehensive. A mechanistic understanding of these interactions will provide important insights into the strategies of bacterial pathogens for survival in and colonization of the host.…”

Inhibition of WAVE Regulatory Complex Activation by a Bacterial Virulence Effector Counteracts Pathogen Phagocytosis

“…To cause disease, they inject a cocktail of virulence effectors into host cells via a type 3 secretion system (T3SS) to enable cell-surface colonization on intestinal epithelia where the pathogen forms lesions characterized by the destruction of brush border microvillii. Here, the bacteria encounter macrophages that infiltrate sites of infection yet EPEC and EHEC are able to block their own phagocytosis through the injected virulence effectors (Santos and Finlay, 2015). Indeed, mutants of type 3 secretion are phagocytosed by macrophages (Goosney et al., 1999, Marchès et al., 2008).…”

“…Indeed, mutants of type 3 secretion are phagocytosed by macrophages (Goosney et al., 1999, Marchès et al., 2008). Four virulence effectors are known to contribute to anti-phagocytosis (Santos and Finlay, 2015); EspB interacts with the actin binding motor protein myosin-1c (Iizumi et al., 2007), EspF inhibits PI3 kinase signaling (Celli et al., 2001), EspH inhibits the Dbl subfamily of Rho guanine nucleotide exchange factors (GEFs) (Dong et al., 2010) and EspJ impedes phagocytosis through inhibition of Src kinase activity (Young et al., 2014). …”