A Rapid Change in Virulence Gene Expression during the Transition from the Intestinal Lumen into Tissue Promotes Systemic Dissemination of Salmonella

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Abstract
Bacterial pathogens causing systemic disease commonly evolve from organisms associated with localized infections but differ from their close relatives in their ability to overcome mucosal barriers by mechanisms that remain incompletely understood. Here we investigated whether acquisition of a regulatory gene, tviA, contributed to the ability of Salmonella enterica serotype Typhi to disseminate from the intestine to systemic sites of infection during typhoid fever. To study the consequences of acquiring a new regulator by horizontal gene transfer, tviA was introduced into the chromosome of S. enterica serotype Typhimurium, a closely related pathogen causing a localized gastrointestinal infection in immunocompetent individuals. TviA repressed expression of flagellin, a pathogen associated molecular pattern (PAMP), when bacteria were grown at osmotic conditions encountered in tissue, but not at higher osmolarity present in the intestinal lumen. TviA-mediated flagellin repression enabled bacteria to evade sentinel functions of human model epithelia and resulted in increased bacterial dissemination to the spleen in a chicken model. Collectively, our data point to PAMP repression as a novel pathogenic mechanism to overcome the mucosal barrier through innate immune evasion. Some bacterial species contain pathogenic strains that are closely related genetically, but cause diseases that differ dramatically in their clinical presentation. One such species is Salmonella enterica, which contains non-typhoidal serotypes associated with a localized gastroenteritis and serotype Typhi (S. Typhi), the causative agent of a severe systemic infection termed typhoid fever. Conventional wisdom holds, that the ability of S. Typhi to overcome mucosal barriers and spread systemically in immunocompetent individuals evolved through acquisition of new virulence factors, which are absent from non-typhoidal Salmonella serotypes. Here, we demonstrate that acquisition of a regulatory gene, tviA, by S. Typhi alters expression of existing virulence factors (the flagellar regulon) such that molecular structures that are detected by the host innate immune are repressed after entering tissue. We propose that this mechanism contributes to innate immune evasion by S. Typhi, thereby promoting systemic dissemination.

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