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Type VI secretion system-associated gene clusters contribute to pathogenesis of Salmonella enterica serovar Typhimurium.

ABSTRACT: The enteropathogen Salmonella enterica serovar Typhimurium employs a suite of tightly regulated virulence factors within the intracellular compartment of phagocytic host cells resulting in systemic dissemination in mice. A type VI secretion system (T6SS) within Salmonella pathogenicity island 6 (SPI-6) has been implicated in this process; however, the regulatory inputs and the roles of noncore genes in this system are not well understood. Here we describe four clusters of noncore T6SS genes in SPI-6 based on a comparative relationship with the T6SS-3 of Burkholderia mallei and report that the disruption of these genes results in defects in intracellular replication and systemic dissemination in mice. In addition, we show that the expression of the SPI-6-encoded Hcp and VgrG orthologs is enhanced during late stages of macrophage infection. We identify six regions that are transcriptionally active during cell infections and that have regulatory contributions from the regulators of virulence SsrB, PhoP, and SlyA. We show that levels of protein expression are very weak under in vitro conditions and that expression is not enhanced upon the deletion of ssrB, phoP, slyA, qseC, ompR, or hfq, suggesting an unknown activating factor. These data suggest that the SPI-6 T6SS has been integrated into the Salmonella Typhimurium virulence network and customized for host-pathogen interactions through the action of noncore genes.

SUBMITTER: Mulder DT

PROVIDER: S-EPMC3370595 | biostudies-literature | 2012 Jun

REPOSITORIES: biostudies-literature

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Type VI secretion system-associated gene clusters contribute to pathogenesis of Salmonella enterica serovar Typhimurium.

Mulder David T DT Cooper Colin A CA Coombes Brian K BK

Infection and immunity 20120409 6

The enteropathogen Salmonella enterica serovar Typhimurium employs a suite of tightly regulated virulence factors within the intracellular compartment of phagocytic host cells resulting in systemic dissemination in mice. A type VI secretion system (T6SS) within Salmonella pathogenicity island 6 (SPI-6) has been implicated in this process; however, the regulatory inputs and the roles of noncore genes in this system are not well understood. Here we describe four clusters of noncore T6SS genes in S ...[more]

PMID: 22493086

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Project description:Salmonella must rapidly adapt to various niches in the host during infection. Relevant virulence factors must be appropriately induced, and systems that are detrimental in a particular environment must be turned off. Salmonella infects intestinal epithelial cells using a type 3 secretion system (T3SS) encoded on Salmonella pathogenicity island 1 (SPI1). The system is controlled by three AraC-like regulators, HilD, HilC, and RtsA, which form a complex feed-forward loop to activate expression of hilA, encoding the main transcriptional regulator of T3SS structural genes. This system is tightly regulated, with many of the activating signals acting at the level of hilD translation or HilD protein activity. Once inside the phagosomes of epithelial cells, or in macrophages during systemic stages of disease, the SPI1 T3SS is no longer required or expressed. Here, we show that the PhoPQ two-component system, critical for intracellular survival, appears to be the primary mechanism by which Salmonella shuts down the SPI1 T3SS. PhoP negatively regulates hilA through multiple distinct mechanisms: direct transcriptional repression of the hilA promoter, indirect transcriptional repression of both the hilD and rtsA promoters, and activation of the small RNA (sRNA) PinT. Genetic analyses and electrophoretic mobility shift assays suggest that PhoP specifically binds the hilA promoter to block binding of activators HilD, HilC, and RtsA as a mechanism of repression.IMPORTANCESalmonella is one of the most common foodborne pathogens, causing an estimated 1.2 million illnesses per year in the United States. A key step in infection is the activation of the bacterial invasion machinery, which induces uptake of the bacterium into epithelial cells and leads to induction of inflammatory diarrhea. Upon entering the vacuolar compartments of host cells, Salmonella senses an environmental transition and represses the invasion machinery with a two-component system relevant for survival within the vacuole. This adaptation to specific host niches is an important example of how signals are integrated for survival of the pathogen.

Dataset Information

Type VI secretion system-associated gene clusters contribute to pathogenesis of Salmonella enterica serovar Typhimurium.

Publications

Type VI secretion system-associated gene clusters contribute to pathogenesis of Salmonella enterica serovar Typhimurium.

Similar Datasets

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