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The Enteropathogenic E. coli Effector EspB Facilitates Microvillus Effacing and Antiphagocytosis by Inhibiting Myosin Function

Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, 4259 Nagatsuta-cho, Midori-ku, Yokohama 226-8501, Japan.
Cell host & microbe (Impact Factor: 12.19). 01/2008; 2(6):383-92. DOI: 10.1016/j.chom.2007.09.012
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ABSTRACT Enteropathogenic Escherichia coli (EPEC) destroys intestinal microvilli and suppresses phagocytosis by injecting effectors into infected cells through a type III secretion system (TTSS). EspB, a component of the TTSS, is also injected into the cytoplasm of host cells. However, the physiological functions of EspB within the host cell cytoplasm remain unclear. We show that EspB binds to myosins, which are a superfamily of proteins that interact with actin filaments and mediate essential cellular processes, including microvillus formation and phagocytosis. EspB inhibits the interaction of myosins with actin, and an EspB mutant that lacks the myosin-binding region maintained its TTSS function but could not induce microvillus effacing or suppress phagocytosis. Moreover, the myosin-binding region of EspB is essential for Citrobacter rodentium, an EPEC-related murine pathogen, to efficiently infect mice. These results suggest that EspB inhibits myosin functions and thereby facilitates efficient infection by EPEC.

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Available from: Hiroshi Handa, Aug 27, 2015
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    • "EHEC colonizes the intestine with the aid of a type III secretion system (T3SS) which enables the bacteria to establish a tight adherence to enterocytes and to modify their cytoskeletal proteins, leading to the characteristic attaching and effacing lesion [8]. EspB is a T3SS protein that plays a central role in mediating the EHEC enterocyte adherence [8] [9] [10] [11] [12]. Moreover, EspB is highly immunogenic in human patients [13] [14] [15] and in infected or vaccinated animals [13] [16]. "
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    • "*Indicates statistical significance (P < 0.05) using oneway ANOVA followed by Tukey's multiple comparison test of TirMC- Ub transfected cells compared to untreated and TirMC transfected host cells. proposed to block EPEC uptake by macrophages via a Tir-independent mechanism (Celli et al., 2000; Iizumi et al., 2007; Dong et al., 2010). It is not understood whether this is the case with infections of nonphagocytes but could constitute another tactic to avoid internalization . "
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    • "IgG-and complement receptor-mediated phagocytosis, but the mechanism remains completely unknown (Marches et al, 2008). The TTSS translocator protein EspB does this by targeting the host myosin (Iizumi et al, 2007), but it is neither solely responsible nor sufficient for the antiphagocytosis function of EPEC (Dean and Kenny, 2009). Therefore, EspH might function together with EspF and EspB to block macrophage phagocytosis by targeting different host processes, thereby promoting bacterial survival in the host. "
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    ABSTRACT: Bacterial pathogens often harbour a type III secretion system (TTSS) that injects effector proteins into eukaryotic cells to manipulate host processes and cause diseases. Identification of host targets of bacterial effectors and revealing their mechanism of actions are crucial for understating bacterial virulence. We show that EspH, a type III effector conserved in enteric bacterial pathogens including enteropathogenic Escherichia coli (EPEC), enterohaemorrhagic E. coli and Citrobacter rodentium, markedly disrupts actin cytoskeleton structure and induces cell rounding up when ectopically expressed or delivered into HeLa cells by the bacterial TTSS. EspH inactivates host Rho GTPase signalling pathway at the level of RhoGEF. EspH directly binds the DH-PH domain in multiple RhoGEFs, which prevents their binding to Rho and thereby inhibits nucleotide exchange-mediated Rho activation. Consistently, infection of mouse macrophages with EPEC harbouring EspH attenuates phagocytosis of the bacteria as well as FcgammaR-mediated phagocytosis. EspH represents the first example of targeting RhoGEFs by bacterial effectors, and our results also reveal an unprecedented mechanism used by enteric pathogens to counteract the host defence system.
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