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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

Hypothetical model for the combined effects of SpvB, SpvC, and SseL to promote Salmonella virulence. In this model, SpvB, SpvC, and SseL could act by different biochemical mechanisms to inhibit NADPH oxidase recruitment to the phagosome and also to promote host cell apoptosis. The overall effect of host cell apoptosis may to be promote cell-to-cell spread of the infection, since extracellular antibiotics such as gentamicin, and phagocytosis of extracellular bacteria by neutrophils, are not able to terminate infections with Salmonella strains that express spv genes. This model would provide an explanation for the experimental and clinical evidence that CD4 T cells and IFN-gamma are required to control infections due to spv+ Salmonella, likely involving macrophage activation and killing of intracellular bacteria.
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Figure 3: Hypothetical model for the combined effects of SpvB, SpvC, and SseL to promote Salmonella virulence. In this model, SpvB, SpvC, and SseL could act by different biochemical mechanisms to inhibit NADPH oxidase recruitment to the phagosome and also to promote host cell apoptosis. The overall effect of host cell apoptosis may to be promote cell-to-cell spread of the infection, since extracellular antibiotics such as gentamicin, and phagocytosis of extracellular bacteria by neutrophils, are not able to terminate infections with Salmonella strains that express spv genes. This model would provide an explanation for the experimental and clinical evidence that CD4 T cells and IFN-gamma are required to control infections due to spv+ Salmonella, likely involving macrophage activation and killing of intracellular bacteria.

Mentions: Early in the analysis of the spv genes, genetic studies indicated that both SpvB and SpvC are required for the virulence phenotype encoded by the spv region (Roudier et al., 1992). A model to account for this finding is proposed in Figure 3. In this model, SpvB and SpvC act by different biochemical mechanisms, but they affect the same cellular pathways involved in the pathogenesis of intracellular Salmonella infection. Both SpvB and SpvC are translocated into the host cell cytoplasm by the SPI-2 TTSS (Browne et al., 2008; Mazurkiewicz et al., 2008). Actin depolymerization and induction of apoptosis are major effects of SpvB during intracellular Salmonella infection (Libby et al., 2000; Lesnick et al., 2001; Browne et al., 2002). Recent studies have shown that the NADPH oxidase associates with actin filaments during the organization and assembly of the oxidase on the membrane (elBenna et al., 1994; Allen et al., 1999; Zhan et al., 2004; Tamura et al., 2006), and wild-type Salmonella decreases NADPH oxidase recruitment to the phagosome by an SPI-2-dependent mechanism (Vazquez-Torres et al., 2000; Gallois et al., 2001). Therefore, SpvB-mediated actin depolymerization may decrease oxidase assembly and recruitment to the phagosome, and therefore could decrease oxidative killing of Salmonella. The second effect of SpvB-mediated actin depolymerization is to induce apoptosis (Libby et al., 2000; Lesnick et al., 2001). The phosphothreonine lyase activity of SpvC acts to decrease MAP kinase signaling, and inhibition of p38 has been demonstrated. As proposed in Figure 3, SpvC inhibition of the p38 MAP kinase isoform would block the synthesis of anti-apoptotic factors and therefore trigger apoptosis, in concert with the effects of SpvB. Macrophage apoptosis is one potential common pathway for the actions of SpvB and SpvC. In addition, SpvC may block the pro-inflammatory signaling function of the MAP kinase isoforms, leading to lower levels of key macrophage-activating cytokines such as TNF. Salmonella infections are known to be more severe in TNF-deficient mice (Vazquez-Torres et al., 2001). TNF has been shown promote localization of the NADPH oxidase to the phagosome of Salmonella-infected macrophages (Vazquez-Torres et al., 2001). Furthermore, the MAP kinase p38 has a direct effect in promoting oxidase assembly through phosphorylation of the p47 phox subunit (Laroux et al., 2005). Therefore, SpvC could act in concert with SpvB to block the recruitment of a functional NADPH oxidase to the phagosome. The SpvB and SpvC effects may be enhanced by the chromosomal sseL gene product, which further promotes apoptosis and decreases macrophage activation through blockade of NF-κB activity.


The Role of the spv Genes in Salmonella Pathogenesis.

Guiney DG, Fierer J - Front Microbiol (2011)

Hypothetical model for the combined effects of SpvB, SpvC, and SseL to promote Salmonella virulence. In this model, SpvB, SpvC, and SseL could act by different biochemical mechanisms to inhibit NADPH oxidase recruitment to the phagosome and also to promote host cell apoptosis. The overall effect of host cell apoptosis may to be promote cell-to-cell spread of the infection, since extracellular antibiotics such as gentamicin, and phagocytosis of extracellular bacteria by neutrophils, are not able to terminate infections with Salmonella strains that express spv genes. This model would provide an explanation for the experimental and clinical evidence that CD4 T cells and IFN-gamma are required to control infections due to spv+ Salmonella, likely involving macrophage activation and killing of intracellular bacteria.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 3: Hypothetical model for the combined effects of SpvB, SpvC, and SseL to promote Salmonella virulence. In this model, SpvB, SpvC, and SseL could act by different biochemical mechanisms to inhibit NADPH oxidase recruitment to the phagosome and also to promote host cell apoptosis. The overall effect of host cell apoptosis may to be promote cell-to-cell spread of the infection, since extracellular antibiotics such as gentamicin, and phagocytosis of extracellular bacteria by neutrophils, are not able to terminate infections with Salmonella strains that express spv genes. This model would provide an explanation for the experimental and clinical evidence that CD4 T cells and IFN-gamma are required to control infections due to spv+ Salmonella, likely involving macrophage activation and killing of intracellular bacteria.
Mentions: Early in the analysis of the spv genes, genetic studies indicated that both SpvB and SpvC are required for the virulence phenotype encoded by the spv region (Roudier et al., 1992). A model to account for this finding is proposed in Figure 3. In this model, SpvB and SpvC act by different biochemical mechanisms, but they affect the same cellular pathways involved in the pathogenesis of intracellular Salmonella infection. Both SpvB and SpvC are translocated into the host cell cytoplasm by the SPI-2 TTSS (Browne et al., 2008; Mazurkiewicz et al., 2008). Actin depolymerization and induction of apoptosis are major effects of SpvB during intracellular Salmonella infection (Libby et al., 2000; Lesnick et al., 2001; Browne et al., 2002). Recent studies have shown that the NADPH oxidase associates with actin filaments during the organization and assembly of the oxidase on the membrane (elBenna et al., 1994; Allen et al., 1999; Zhan et al., 2004; Tamura et al., 2006), and wild-type Salmonella decreases NADPH oxidase recruitment to the phagosome by an SPI-2-dependent mechanism (Vazquez-Torres et al., 2000; Gallois et al., 2001). Therefore, SpvB-mediated actin depolymerization may decrease oxidase assembly and recruitment to the phagosome, and therefore could decrease oxidative killing of Salmonella. The second effect of SpvB-mediated actin depolymerization is to induce apoptosis (Libby et al., 2000; Lesnick et al., 2001). The phosphothreonine lyase activity of SpvC acts to decrease MAP kinase signaling, and inhibition of p38 has been demonstrated. As proposed in Figure 3, SpvC inhibition of the p38 MAP kinase isoform would block the synthesis of anti-apoptotic factors and therefore trigger apoptosis, in concert with the effects of SpvB. Macrophage apoptosis is one potential common pathway for the actions of SpvB and SpvC. In addition, SpvC may block the pro-inflammatory signaling function of the MAP kinase isoforms, leading to lower levels of key macrophage-activating cytokines such as TNF. Salmonella infections are known to be more severe in TNF-deficient mice (Vazquez-Torres et al., 2001). TNF has been shown promote localization of the NADPH oxidase to the phagosome of Salmonella-infected macrophages (Vazquez-Torres et al., 2001). Furthermore, the MAP kinase p38 has a direct effect in promoting oxidase assembly through phosphorylation of the p47 phox subunit (Laroux et al., 2005). Therefore, SpvC could act in concert with SpvB to block the recruitment of a functional NADPH oxidase to the phagosome. The SpvB and SpvC effects may be enhanced by the chromosomal sseL gene product, which further promotes apoptosis and decreases macrophage activation through blockade of NF-κB activity.

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