<i>Yersinia enterocolitica</i>
            induces apoptosis in macrophages by a process requiring functional type III secretion and  translocation mechanisms and involving YopP,  presumably acting as an effector protein

Mills, Scott D.; Boland, Anne; Sory, Marie‐Paule; Smissen, Patrick Van Der; Kerbourch, C; Finlay, B. Brett; Cornelis, Guy R.

doi:10.1073/pnas.94.23.12638

Cited by 279 publications

(238 citation statements)

References 39 publications

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“…YopJ is the only Yop effector required for the induction of apoptosis in murine macrophages (Mills et al, 1997;Monack et al, 1997). However, induction of apoptosis seems to be independent of the role of YopJ in perturbing signalling pathways, as YopJ does not induce apoptosis in fibroblasts even though it disrupts the same signalling pathways within fibroblasts.…”

Section: Yopjmentioning

confidence: 97%

Yersinia effectors target mammalian signalling pathways

2002

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SummaryAnimals have an immune system to fight off challenges from both viruses and bacteria. The first line of defence is innate immunity, which is composed of cells that engulf pathogens as well as cells that release potent signalling molecules to activate an inflammatory response and the adaptive immune system. Pathogenic bacteria have evolved a set of weapons, or effectors, to ensure survival in the host. Yersinia spp. use a type III secretion system to translocate these effector proteins, called Yops, into the host. This report outlines how Yops thwart the signalling machinery of the host immune system. Introduction Innate immunity and signallingInnate immunity is the first line of defence against bacterial and viral infection (for a review of innate immunity, see Medzhitov and Janeway, 2000). The cells involved in the immune response use a wide variety of signalling cascades to activate processes such as phagocytosis, cytokine production and release and production of reactive oxygen species. In addition to eliminating pathogens, the innate immune system activates the adaptive immune response through the presentation of foreign peptides to T cells.Phagocytosis is an essential component of the innate immune system (May and Machesky, 2001). Rearrangement of the actin cytoskeleton during phagocytosis is mediated by the recruitment of proteins that function in actin rearrangement; these include paxillin, p130Cas and focal adhesion kinase (FAK) (Greenberg et al., 1990;Allen and Aderem, 1996). These proteins may form through M cells (microfold cells), which are specialized cells that take up foreign antigens, in intestinal Peyer's patches (Autenrieth and Firsching, 1996). Recognition of Yersinia by M cells is mediated via b1 integrins on the M-cell plasma membrane and the invasin protein of Yersinia (Marra and Isberg, 1997;Clark et al., 1998). Once Yersinia has penetrated the M cells, it can localize in the lymphoid tissue of its host.The recently sequenced genome of Y. pestis (Parkhill et al., 2001) suggests that many of the genes that Yersinia uses during infection and invasion, including adhesins, secretion systems and insecticidal toxins, have been acquired from other bacteria and viruses. Furthermore, all three pathogenic species of Yersinia harbour an extrachromosomal plasmid of 70 kb that is essential for virulence (Portnoy and Martinez, 1985). This plasmid contains the genes of a type III secretion system, a translocation apparatus highly conserved among pathogenic Gram-negative bacteria (for a review, see Cornelis, 1998). This secretion system is responsible for the translocation of the Yersinia effectors, termed Yops, into the host cell. Once inside the host cell, Yops carry out disruption of signalling cascades that activate the processes of phagocytosis, cytokine release and respiratory burst. Six Yop effectors have been identified (YopH, YopE, YopJ/P, YpkA/YopO, YopT and YopM). Some of these effectors are known to function in the downregulation of critical signalling cascades of the immune system (Fig...

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Section: Yopjmentioning

confidence: 97%

Yersinia effectors target mammalian signalling pathways

2002

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Section: Introductionmentioning

confidence: 99%

“…In contrast, Salmonella and Shigella can survive within macrophages as well as kill macrophages, depending on the physiological state of the macrophage (Navarre & Zychlinsky, 2000). Finally, Yersinia is also known to induce macrophage death (Hersh et al, 1999;Mills et al, 1997;Palmer et al, 1999).Apoptosis, pyroptosis, autophagy and oncosis are four distinct pathways used by bacteria to trigger host cell death (Fink & Cookson, 2005). The pathogenic outcomes of these four pathways are distinct, whereby cell death by an apoptotic or autophagy pathway occurs without significant tissue disruption and inflammation, while host cell death by oncosis and pyroptosis leads to secretion of inflammatory cytokines, such as interleukin (IL)-1b and IL-8, and subsequent recruitment of activated neutrophils to the site of infection (Navarre & Zychlinsky, 2000).…”

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Type III secretion system 1 of Vibrio parahaemolyticus induces oncosis in both epithelial and monocytic cell lines

2009

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The Vibrio parahaemolyticus type III secretion system 1 (T3SS1) induces cytotoxicity in mammalian epithelial cells. We characterized the cell death phenotype in both epithelial (HeLa) and monocytic (U937) cell lines following infection with V. parahaemolyticus. Using a combination of the wild-type strain and gene knockouts, we confirmed that V. parahaemolyticus strain NY-4 was able to induce cell death in both cell lines via a T3SS1-dependent mechanism. Bacterial contact, but not internalization, was required for T3SS1-induced cytotoxicity. The mechanism of cell death involves formation of a pore structure on the surface of infected HeLa and U937 cells, as demonstrated by cellular swelling, uptake of cell membrane-impermeable dye and protection of cytotoxicity by osmoprotectant (PEG3350). Western blot analysis showed that poly ADP ribose polymerase (PARP) was not cleaved and remained in its full-length active form. This result was evident for seven different V. parahaemolyticus strains. V. parahaemolyticus-induced cytotoxicity was not inhibited by addition of the pan-caspase inhibitor carbobenzoxy-valyl-alanyl-aspartyl-[O-methyl]-fluoromethylketone (Z-VAD-FMK) or the caspase-1 inhibitor N-acetyl-tyrosyl-valylalanyl-aspartyl-aldehyde (Ac-YVAD-CHO); thus, caspases were not involved in T3SS1-induced cytotoxicity. DNA fragmentation was not evident following infection and autophagic vacuoles were not observed after monodansylcadaverine staining. We conclude that T3SS1 of V. parahaemolyticus strain NY-4 induces a host cell death primarily via oncosis rather than apoptosis, pyroptosis or autophagy. INTRODUCTIONVibrio parahaemolyticus is a Gram-negative food-borne pathogen that is commonly associated with consumption of raw or undercooked seafood (Joseph et al., 1982). Symptoms of infection include diarrhoea, nausea, vomiting, headache, fever and chills. In addition to typical gastrointestinal infections, approximately 5 % of V. parahaemolyticus infections advance to septicaemia (Hlady & Klontz, 1996) and these infections may be fatal, especially in immunocompromised patients or those with a preexisting medical condition such as liver disease or diabetes (Yeung & Boor, 2004).Thermostable direct haemolysin (TDH) is considered the primary virulence factor in V. parahaemolyticus. In addition to its ability to form pores in red blood cells, TDH causes increased short circuit current, increased Cl 2 secretion in human colonic epithelial cells, and enhanced Ca 2+ entry from the extracellular medium (Takahashi et al., 2001). An early study of a tdh deletion mutant demonstrated significantly reduced ability to cause fluid accumulation in ileal loops of a rabbit model (Nishibuchi et al., 1992). In contrast, Park et al. (2004) showed that a tdh deletion mutant has the ability to cause fluid accumulation in the ligated intestine of rabbits. Furthermore, both TDH-positive and -negative strains of V. parahaemolyticus can disrupt the epithelial tight junction, a precursor to dissemination of bacteria into the circulation (Lynch et a...

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“…These proteins share sequence and structural homology with the cysteine proteases from adenovirus and the ubiquitin-like protein proteases from eukaryotes. One example is the Yersinia effector YopJ that has been shown to block the innate immune response in infected mammalian cells (macrophages) (5). YopJ inhibits the activation of mitogen-activated protein kinase (MAPK) 3 kinases and the I B kinases (IKK), resulting in inhibition of MAPK and NF-B signaling pathways (6).…”

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confidence: 99%

Cutting Edge: Salmonella AvrA Effector Inhibits the Key Proinflammatory, Anti-Apoptotic NF-κB Pathway

Collier-Hyams

Zeng

Sun

et al. 2002

The Journal of Immunology

257

230

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Secreted prokaryotic effector proteins have evolved to modulate the cellular functions of specific eukaryotic hosts. Generally, these proteins are considered virulence factors that facilitate parasitism. However, in certain plant and insect eukaryotic/prokaryotic relationships, effector proteins are involved in the establishment of commensal or symbiotic interactions. In this study, we report that the AvrA protein from Salmonella typhimurium, a common enteropathogen of humans, is an effector molecule that inhibits activation of the key proinflammatory NF-κB transcription factor and augments apoptosis in human epithelial cells. This activity is similar but mechanistically distinct from that described for YopJ, an AvrA homolog expressed by the bacterial pathogen Yersinia. We suggest that AvrA may limit virulence in vertebrates in a manner analogous to avirulence factors in plants, and as such, is the first bacterial effector from a mammalian pathogen that has been ascribed such a function.

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Yersinia enterocolitica induces apoptosis in macrophages by a process requiring functional type III secretion and translocation mechanisms and involving YopP, presumably acting as an effector protein

Cited by 279 publications

References 39 publications

Yersinia effectors target mammalian signalling pathways

Yersinia effectors target mammalian signalling pathways

Type III secretion system 1 of Vibrio parahaemolyticus induces oncosis in both epithelial and monocytic cell lines

Cutting Edge: Salmonella AvrA Effector Inhibits the Key Proinflammatory, Anti-Apoptotic NF-κB Pathway

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