Abstract
Vaccination with Salmonella enterica serovar Typhimurium lacking DNA adenine methyltransferase confers cross-protective immunity against multiple Salmonella serotypes. The mechanistic basis is thought to be associated with the de-repression of genes that are tightly regulated when transiting from one microenvironment to another. This de-repression provides a potential means for the production of a more highly expressed and stable antigenic repertoire capable of inducing cross-protective immune responses. To identify genes encoding proteins that may contribute to cross-protective immunity, we used a Salmonella Typhimurium DNA adenine methyltransferase mutant strain (UK-1 dam mutant) derived from the parental UK-1 strain, and assessed the transcriptional profile of the UK-1 dam mutant and UK-1 strain grown under conditions that simulate the intestinal or endosomal microenvironments encountered during the infective process. As expected, the transcriptional profile of the UK-1 dam mutant identified a set of genes more transcriptionally active when compared directly to UK-1, and stably transcribed in biologically relevant culture conditions. Further, 22% of these genes were more highly transcribed in comparison to two other clinically-relevant Salmonella serovars. The strategy employed here helps to identify potentially conserved proteins produced by the UK-1 dam mutant that stimulate and/or modulate the development of cross-protective immune responses toward multiple Salmonella serotypes.
Highlights
Non-typhoidal Salmonella serotypes, including Salmonella enterica serovar Typhimurium and Salmonella enterica serovar Enteriditis, are food-borne pathogens, and important causes of bacterial enteric disease in both humans and livestock
When grown in low phosphate and magnesium concentration (LPM) medium, 317 genes were highly transcribed in the UK-1 dam mutant whereas only 82 genes were highly transcribed in the wt parent strain (Figure 1b)
Ninety-four genes (Table 1), referred to as Gene Set A, were identified that (i) had significantly higher relative transcription by the UK-1 dam mutant in both culture conditions when compared with the wt parent strain; and (ii) were stably transcribed between HSLB and LPM media in the intra-strain comparison (Figure 3). We focused on this set of genes because their transcription is always “on” in the mutant regardless of environmental stimuli, and coupled with high relative transcription compared to the wt parent strain, could represent an important set of stably expressed target proteins promoting the development of cross-protection elicited by the UK-1 dam mutant
Summary
Non-typhoidal Salmonella serotypes, including Salmonella enterica serovar Typhimurium and Salmonella enterica serovar Enteriditis, are food-borne pathogens, and important causes of bacterial enteric disease in both humans and livestock. In addition to serotype diversity, exposure of Salmonella to diverse microenvironments within the host serves as a cue to modulate its own gene transcription leading to differences in protein expression [5,6,7,8]. These changes in pathogen-expressed proteins in response to environmental cues result in skewed immune responses toward serotype-specific proteins which, in turn, contribute to the lack of cross-protection [9,10,11,12]
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