Abstract
The invasion of epithelial cells by Salmonella enterica serovar Typhimurium is a very tightly regulated process. Signaling cascades triggered by different environmental and physiological signals converge to control HilD, an AraC regulator that coordinates the expression of several virulence factors. The expression of hilD is modulated at several steps of the expression process. Here, we report that the invasion of epithelial cells by S. Typhimurium strains lacking the Gre factors, GreA and GreB, is impaired. By interacting with the RNA polymerase secondary channel, the Gre factors prevent backtracking of paused complexes to avoid arrest during transcriptional elongation. Our results indicate that the Gre factors are required for the expression of the bacterial factors needed for epithelial cell invasion by modulating expression of HilD. This regulation does not occur at transcription initiation and depends on the capacity of the Gre factors to prevent backtracking of the RNA polymerase. Remarkably, genetic analyses indicate that the 3’-untranslated region (UTR) of hilD is required for Gre-mediated regulation of hilD expression. Our data provide new insight into the complex regulation of S. Typhimurium virulence and highlight the role of the hilD 3’-UTR as a regulatory motif.
Highlights
Typhimurium invades epithelial cells, a process that requires the coordinated expression of a set of genes
HilD-mediated regulation is not restricted to the Salmonella pathogenicity islands (SPIs)-1 genes, as HilD modulates the expression of genes located outside this genetic locus such as sopE, which encodes an effector protein secreted via three secretion systems (TTSS)-1, and ssrAB, which encodes the twocomponent system that acts as the central positive regulator of the SPI-2 genes [10,17,18]
We found that the Gre factors are required for the proper expression of the SPI-1 effector proteins and subsequent cell invasion as well as organ colonization in a mouse model of systemic infection
Summary
SPI-1 contains genes required during the first steps of epithelial cell infection, while SPI-2 encodes genes needed for S. HilA induces the expression of the regulator InvF, a transcriptional activator of sic/ sip operons, encoding effector proteins [11,12]. HilA transcriptional expression is autoregulated and tightly modulated by the combined action of three AraC-like transcriptional activators: HilC, HilD and RtsA [13,14]. Each of these three regulators are positively autoregulated and can induce the expression of the other two, producing a positive feed-forward loop that controls SPI-1 gene expression [15].
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