Abstract
Vibrio parahaemolyticus is the leading cause of seafood-borne diarrheal diseases. Experimental overproduction of a type 3 secretion system (T3SS1) in this pathogen leads to decreased intestinal colonization, which suggests that T3SS1 repression is required for maximal virulence. However, the mechanisms by which T3SS1 is repressed in vivo are unclear. Here, we show that host-derived nitrite modifies the activity of a bacterial histidine kinase and mediates T3SS1 repression. More specifically, nitrite activates histidine kinase sensor VbrK through S-nitrosylation on cysteine 86, which results in downregulation of the entire T3SS1 operon through repression of its positive regulator exsC. Replacement of cysteine 86 with a serine (VbrK C86S mutant) leads to increased expression of inflammatory cytokines in infected Caco-2 cells. In an infant rabbit model of infection, the VbrK C86S mutant induces a stronger inflammatory response at the early stage of infection, and displays reduced intestinal colonization and virulence at the later stage of infection, in comparison with the parent strain. Our results indicate that the pathogen V. parahaemolyticus perceives nitrite as a host-derived signal and responds by downregulating a proinflammatory factor (T3SS1), thus enhancing intestinal colonization and virulence.
Highlights
Vibrio parahaemolyticus is the leading cause of seafood-borne diarrheal diseases
To test the hypothesis that one of the twocomponent system (TCS) is involved in T3SS1 regulation, we constructed 48 mutants in which each predicted histidine kinase (HK) was individually deleted from the chromosome of V. parahaemolyticus
To determine if T3SS2 and thermostable direct hemolysin (TDH) have confounding effect, we used POR3 strain as the parental strain in the culture infection assay, and the results showed that T3SS1 gene expression can be repressed in POR3, but not in POR3ΔvbrK (Supplementary Fig. 7e, f), consistent with the results when WT was used as parental strain (Fig. 6c–f), indicating that T3SS2 and TDH do not affect the ability of VbrK to sense nitrite and repress T3SS1 gene expression
Summary
Vibrio parahaemolyticus is the leading cause of seafood-borne diarrheal diseases. Experimental overproduction of a type 3 secretion system (T3SS1) in this pathogen leads to decreased intestinal colonization, which suggests that T3SS1 repression is required for maximal virulence. Our results indicate that the pathogen V. parahaemolyticus perceives nitrite as a host-derived signal and responds by downregulating a proinflammatory factor (T3SS1), enhancing intestinal colonization and virulence. The type 3 secretion system (T3SS) is an important virulence determinant employed by a variety of gram-negative bacterial pathogens to cause diseases in humans. In the infant rabbit infection model, T3SS2 plays an essential role in intestinal colonization and diarrheal disease[11] and these two processes can be genetically separated by an internal fragment of the effector VopZ19. Deletion of the effector VopC resulted in significant reduction in bacterial mucosal invasion and gastroenteritis, but not pathology in this germfree mouse model[20] Together, these results highlight the importance of T3SS2 in the pathogenesis of V. parahaemolyticus in vivo
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