Modulation of Host Cell Processes by T3SS Effectors

Abstract

Two of the enteric Escherichia coli pathotypes-enteropathogenic E. coli (EPEC) and enterohaemorrhagic E. coli (EHEC)-have a conserved type 3 secretion system which is essential for virulence. The T3SS is used to translocate between 25 and 50 bacterial proteins directly into the host cytosol where they manipulate a variety of host cell processes to establish a successful infection. In this chapter, we discuss effectors from EPEC/EHEC in the context of the host proteins and processes that they target-the actin cytoskeleton, small guanosine triphosphatases and innate immune signalling pathways that regulate inflammation and cell death. Many of these translocated proteins have been extensively characterised, which has helped obtain insights into the mechanisms of pathogenesis of these bacteria and also understand the host pathways they target in more detail. With increasing knowledge of the positive and negative regulation of host signalling pathways by different effectors, a future challenge is to investigate how the specific effector repertoire of each strain cooperates over the course of an infection.

Enteropathogenic Escherichia coli Stimulates Effector-Driven Rapid Caspase-4 Activation in Human Macrophages

“…A/E pathogens typically secrete 25–30 effectors, which subvert various host processes, including opsonophagocytosis, activation of nuclear factor κB (NF-κB), mitogen-activated protein kinases (MAPKs), type I interferons, and cell death ( Pearson et al., 2016 , Shenoy et al., 2018 ). NleB, NleC, NleD, and NleE, which block NF-κB and MAPKs, may also attenuate signaling by IL-1/IL-18 cytokines produced by robust Tir-dependent inflammasome activation.…”

“…Intimate attachment is mediated by the binding of intimin, a bacterial outer membrane adhesin, to the translocated intimin receptor (Tir), which is delivered into mammalian cells via a type III secretion system (T3SS) injectisome ( Kenny et al., 1997 ). The T3SS is encoded by four operons, i.e., locus for enterocyte effacement (LEE) 1–4, and the monocistronic escD gene within the LEE pathogenicity island ( McDaniel et al., 1995 , Elliott et al., 1998 ), and translocates multiple LEE-encoded (e.g., Tir, Map, EspG) and non-LEE- encoded (e.g., EspJ, NleA-F, TccP) effectors that manipulate signaling in the host cell ( Wong et al., 2011 , Pearson et al., 2016 , Shenoy et al., 2018 ). Expression of the T3SS and effector genes can be induced by growing EPEC/EHEC in low-glucose DMEM (DMEM priming) in vitro ( Rosenshine et al., 1996 , Abe et al., 2002 , Furniss and Clements, 2017 ).…”

Vying for the control of inflammasomes: The cytosolic frontier of enteric bacterial pathogen–host interactions

“…Intimate attachment is mediated by strong interactions between intimin on the bacterial surface and Tir (translocated intimin receptor), which is injected into IECs by the T3SS (Frankel & Phillips, 2008;Slater, Sågfors, Pollard, Ruano-Gallego, & Frankel, 2018), all of which are encoded within the locus for enterocyte effacement (LEE) common to A/E pathogens (Frankel et al, 1998). Intimin:Tir interactions lead to Tir clustering and actin polymerisation underneath attached bacteria, which facilitates delivery of other T3SS effectors that subvert mammalian cell processes (Shenoy, Furniss, Goddard, & Clements, 2018). Strain to strain variability in both the repertoire of T3SS effectors and other virulence factors affects the outcome of pathogen-host interactions; haemolysins (such as EhxA) and the Shiga toxins (Stx1 and 2) mentioned herein are exclusively expressed by EHEC.…”

Taming the Triskelion: Bacterial Manipulation of Clathrin

“…The level of bacterial attachment to cells influences the efficiency of effector protein translocation by the T3SS (178). Since many effector proteins act as key virulence factors in their own right, the ability to form pedestals to allow optimal translocation is essential for the success of EPEC (179).…”