The Role of the spv Genes in Salmonella Pathogenesis

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.

Keywords: ADP-ribosylation; CD4; Salmonella; apoptosis; non-typhoid bacteremia; phosphothreonine lyase; spv; virulence.

Figure 1

Map of the spv region found on virulence plasmids in subspecies 1 strains, not drawn to scale. The spvR gene is transcribed separately from the spvABCD genes. SpvR activates transcription at both promoters in concert with the RpoS sigma factor. The expansion shows the general structure of the SpvB protein, with N- and C-terminal domains separated by a run of proline residues (P). EAE denotes residues at the active site for the ADP-ribosylation activity.

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.

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.