Abstract
We know a great deal about the genes used by the model pathogen Salmonella enterica serovar Typhimurium to cause disease, but less about global gene regulation. New tools for studying transcripts at the single nucleotide level now offer an unparalleled opportunity to understand the bacterial transcriptome, and expression of the small RNAs (sRNA) and coding genes responsible for the establishment of infection. Here, we define the transcriptomes of 18 mutants lacking virulence-related global regulatory systems that modulate the expression of the SPI1 and SPI2 Type 3 secretion systems of S. Typhimurium strain 4/74. Using infection-relevant growth conditions, we identified a total of 1257 coding genes that are controlled by one or more regulatory system, including a sub-class of genes that reflect a new level of cross-talk between SPI1 and SPI2. We directly compared the roles played by the major transcriptional regulators in the expression of sRNAs, and discovered that the RpoS (σ38) sigma factor modulates the expression of 23% of sRNAs, many more than other regulatory systems. The impact of the RNA chaperone Hfq upon the steady state levels of 280 sRNA transcripts is described, and we found 13 sRNAs that are co-regulated with SPI1 and SPI2 virulence genes. We report the first example of an sRNA, STnc1480, that is subject to silencing by H-NS and subsequent counter-silencing by PhoP and SlyA. The data for these 18 regulatory systems is now available to the bacterial research community in a user-friendly online resource, SalComRegulon.
Highlights
As well as confirming published regulatory inputs for Salmonella pathogenicity islands, such as the positive role played by Fur in the expression of SPI1, we report, for the first time, the global impact of the FliZ, HilE and PhoB/R transcription factors and identify 124 small RNAs (sRNA) that belong to virulence-associated regulons
We found a subset of genes of known and unknown function that are regulated by both HilD and SsrB, highlighting the cross-talk mechanisms that control Salmonella virulence
We showed that the putative virulence-associated sRNA, STnc1480, is silenced by the nucleoidassociated protein H-NS, and that the transcription factors PhoP and SlyA counteract the repressive effects of H-NS at the STnc1480 promoter
Summary
NTS strains cause bloodstream infections that kill about 20% of patients. This high mortality rate reflects the combination of pre-disposing conditions such as HIV, malaria and malnutrition, and the emergence of invasive NTS strains [2, 3]. The bacteria express a Type III Secretion System (T3SS) encoded on a pathogenicity island (SPI1) that mediates invasion of the host intestinal epithelium. Typhimurium expresses a second T3SS, encoded on a second pathogenicity island (SPI2), which is responsible for its survival and replication in the intracellular environment within the Salmonella containing vacuole (SCV) and for the establishment of systemic infection [4, 5]
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