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The Role of the spv Genes in Salmonella Pathogenesis.

Guiney DG, Fierer J - Front Microbiol (2011)

Bottom Line: The exact mechanisms by which SpvB and SpvC act in concert to enhance virulence are still unclear.SpvB exhibits a cytotoxic effect on host cells and is required for delayed cell death by apoptosis following intracellular infection.Strains isolated from systemic infections of immune compromised patients, particularly HIV patients, usually carry the spv locus, strongly suggesting that CD4 T cells are required to control disease due to Salmonella that are spv positive.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, University of California San Diego School of Medicine La Jolla, CA, USA.

ABSTRACT
Salmonella strains cause three main types of diseases in people: gastroenteritis, enteric (typhoid) fever, and non-typhoid extra-intestinal disease with bacteremia. Genetic analysis indicates that each clinical syndrome requires distinct sets of virulence genes, and Salmonella isolates differ in their constellation of virulence traits. The spv locus is strongly associated with strains that cause non-typhoid bacteremia, but are not present in typhoid strains. The spv region contains three genes required for the virulence phenotype in mice: the positive transcriptional regulator spvR and two structural genes spvB and spvC. SpvB and SpvC are translocated into the host cell by the Salmonella pathogenicity island-2 type-three secretion system. SpvB prevents actin polymerization by ADP-ribosylation of actin monomers, while SpvC has phosphothreonine lyase activity and has been shown to inhibit MAP kinase signaling. The exact mechanisms by which SpvB and SpvC act in concert to enhance virulence are still unclear. SpvB exhibits a cytotoxic effect on host cells and is required for delayed cell death by apoptosis following intracellular infection. Strains isolated from systemic infections of immune compromised patients, particularly HIV patients, usually carry the spv locus, strongly suggesting that CD4 T cells are required to control disease due to Salmonella that are spv positive. This association is not seen with typhoid fever, indicating that the pathogenesis and immunology of typhoid have fundamental differences from the syndrome of non-typhoid bacteremia.

No MeSH data available.


Related in: MedlinePlus

General scheme of pathways affecting delayed apoptosis in Salmonella-infected host cells. Roles for each of the host factors were demonstrated using knockout mice or inhibitors. SpvB is known to be required and presumably acts through actin depolymerization, but the exact mechanism connecting SpvB to the induction of apoptosis remains to be clarified. Although SpvC and SseL have been shown to inhibit p38 and NF-κB respectively, the roles of these effectors in apoptosis is hypothetical at present.
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Figure 2: General scheme of pathways affecting delayed apoptosis in Salmonella-infected host cells. Roles for each of the host factors were demonstrated using knockout mice or inhibitors. SpvB is known to be required and presumably acts through actin depolymerization, but the exact mechanism connecting SpvB to the induction of apoptosis remains to be clarified. Although SpvC and SseL have been shown to inhibit p38 and NF-κB respectively, the roles of these effectors in apoptosis is hypothetical at present.

Mentions: Regulation of apoptosis in macrophages is complex, with competing pathways leading to pro- and anti-apoptotic factors that govern the ultimate outcome. In general, primary macrophages exposed to bacterial products and/or pro-inflammatory, death-inducing cytokines such as TNF become activated rather than undergo apoptosis, due to the induction of factors that favor cell survival (Park et al., 2002; Hsu et al., 2004). Clearly, macrophages have to survive at sites of infection in order to function as immune effector cells. However, certain bacterial pathogens have evolved specific virulence mechanisms that block the pro-survival pathways of macrophages, tipping the balance of signals in favor of apoptosis and resulting in the death of the macrophage. Figure 2 shows a schematic representation of the key pathways leading to the induction of apoptosis during infection of macrophages with Salmonella. For clarity, many factors and co-factors in the individual pathways are not shown. The data in support for this scheme were obtained primarily through the use of macrophages from specific knockout and transgenic mice in combination with specific bacterial mutants. As seen in Figure 2, apoptosis of wild-type macrophages in this system requires the SPI-2 TTSS but not the SPI-1 TTSS (SipB). Therefore, the process of apoptotic cell death clearly differs from pyroptosis dependent on SipB as described above (Fink and Cookson, 2007). Salmonella infection triggers activation of TLR4 by LPS. Although Salmonella produces ligands for other TLRs such as TLR2, TLR5, and TLR9, TLR4 has been shown to be required for apoptosis induced by Salmonella, so we have not shown the other TLRs in this scheme. TLR4 ligation triggers activation of the adapter proteins MyD88 and TRIF (also known as lps2). As seen in Figure 2, the TRIF pathway is a major activator of apoptosis, through a key intermediate kinase, PKR (also known as dsRNA responsive protein kinase because of its involvement in TLR3 signaling). Macrophages deficient in TRIF or PKR show marked reduction in Salmonella-induced apoptosis. PKR activates interferon-response factor-3 (IRF-3) and also phosphorylates eukaryotic translation initiation factor 2α (eIF2α), inhibiting protein synthesis and therefore blocking the expression of anti-apoptotic factors. Macrophages lacking IRF-3, and transgenic knock-in macrophages expressing a mutant eIF2α that is not phosphorylated by PKR both show reduced apoptosis after Salmonella infection (data in reference Hsu et al., 2004). These results clearly establish the TRIF pathway as a major transducer of pro-apoptotic signaling during Salmonella infection.


The Role of the spv Genes in Salmonella Pathogenesis.

Guiney DG, Fierer J - Front Microbiol (2011)

General scheme of pathways affecting delayed apoptosis in Salmonella-infected host cells. Roles for each of the host factors were demonstrated using knockout mice or inhibitors. SpvB is known to be required and presumably acts through actin depolymerization, but the exact mechanism connecting SpvB to the induction of apoptosis remains to be clarified. Although SpvC and SseL have been shown to inhibit p38 and NF-κB respectively, the roles of these effectors in apoptosis is hypothetical at present.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3117207&req=5

Figure 2: General scheme of pathways affecting delayed apoptosis in Salmonella-infected host cells. Roles for each of the host factors were demonstrated using knockout mice or inhibitors. SpvB is known to be required and presumably acts through actin depolymerization, but the exact mechanism connecting SpvB to the induction of apoptosis remains to be clarified. Although SpvC and SseL have been shown to inhibit p38 and NF-κB respectively, the roles of these effectors in apoptosis is hypothetical at present.
Mentions: Regulation of apoptosis in macrophages is complex, with competing pathways leading to pro- and anti-apoptotic factors that govern the ultimate outcome. In general, primary macrophages exposed to bacterial products and/or pro-inflammatory, death-inducing cytokines such as TNF become activated rather than undergo apoptosis, due to the induction of factors that favor cell survival (Park et al., 2002; Hsu et al., 2004). Clearly, macrophages have to survive at sites of infection in order to function as immune effector cells. However, certain bacterial pathogens have evolved specific virulence mechanisms that block the pro-survival pathways of macrophages, tipping the balance of signals in favor of apoptosis and resulting in the death of the macrophage. Figure 2 shows a schematic representation of the key pathways leading to the induction of apoptosis during infection of macrophages with Salmonella. For clarity, many factors and co-factors in the individual pathways are not shown. The data in support for this scheme were obtained primarily through the use of macrophages from specific knockout and transgenic mice in combination with specific bacterial mutants. As seen in Figure 2, apoptosis of wild-type macrophages in this system requires the SPI-2 TTSS but not the SPI-1 TTSS (SipB). Therefore, the process of apoptotic cell death clearly differs from pyroptosis dependent on SipB as described above (Fink and Cookson, 2007). Salmonella infection triggers activation of TLR4 by LPS. Although Salmonella produces ligands for other TLRs such as TLR2, TLR5, and TLR9, TLR4 has been shown to be required for apoptosis induced by Salmonella, so we have not shown the other TLRs in this scheme. TLR4 ligation triggers activation of the adapter proteins MyD88 and TRIF (also known as lps2). As seen in Figure 2, the TRIF pathway is a major activator of apoptosis, through a key intermediate kinase, PKR (also known as dsRNA responsive protein kinase because of its involvement in TLR3 signaling). Macrophages deficient in TRIF or PKR show marked reduction in Salmonella-induced apoptosis. PKR activates interferon-response factor-3 (IRF-3) and also phosphorylates eukaryotic translation initiation factor 2α (eIF2α), inhibiting protein synthesis and therefore blocking the expression of anti-apoptotic factors. Macrophages lacking IRF-3, and transgenic knock-in macrophages expressing a mutant eIF2α that is not phosphorylated by PKR both show reduced apoptosis after Salmonella infection (data in reference Hsu et al., 2004). These results clearly establish the TRIF pathway as a major transducer of pro-apoptotic signaling during Salmonella infection.

Bottom Line: The exact mechanisms by which SpvB and SpvC act in concert to enhance virulence are still unclear.SpvB exhibits a cytotoxic effect on host cells and is required for delayed cell death by apoptosis following intracellular infection.Strains isolated from systemic infections of immune compromised patients, particularly HIV patients, usually carry the spv locus, strongly suggesting that CD4 T cells are required to control disease due to Salmonella that are spv positive.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, University of California San Diego School of Medicine La Jolla, CA, USA.

ABSTRACT
Salmonella strains cause three main types of diseases in people: gastroenteritis, enteric (typhoid) fever, and non-typhoid extra-intestinal disease with bacteremia. Genetic analysis indicates that each clinical syndrome requires distinct sets of virulence genes, and Salmonella isolates differ in their constellation of virulence traits. The spv locus is strongly associated with strains that cause non-typhoid bacteremia, but are not present in typhoid strains. The spv region contains three genes required for the virulence phenotype in mice: the positive transcriptional regulator spvR and two structural genes spvB and spvC. SpvB and SpvC are translocated into the host cell by the Salmonella pathogenicity island-2 type-three secretion system. SpvB prevents actin polymerization by ADP-ribosylation of actin monomers, while SpvC has phosphothreonine lyase activity and has been shown to inhibit MAP kinase signaling. The exact mechanisms by which SpvB and SpvC act in concert to enhance virulence are still unclear. SpvB exhibits a cytotoxic effect on host cells and is required for delayed cell death by apoptosis following intracellular infection. Strains isolated from systemic infections of immune compromised patients, particularly HIV patients, usually carry the spv locus, strongly suggesting that CD4 T cells are required to control disease due to Salmonella that are spv positive. This association is not seen with typhoid fever, indicating that the pathogenesis and immunology of typhoid have fundamental differences from the syndrome of non-typhoid bacteremia.

No MeSH data available.


Related in: MedlinePlus