Credit: NPG

Human-adapted Salmonella enterica subsp. enterica serovar Typhi is the causative agent of the systemic disease typhoid fever, whereas its close relative Salmonella enterica subsp. enterica serovar Typhimurium causes only localized gastroenteritis. Several virulence factors have been associated with the dissemination of S. Typhi, including the virulence-associated (Vi) capsular polysaccharide, which is absent from S. Typhimurium. Now, Wangdi et al. show that S. Typhi uses the Vi capsular polysaccharide to escape neutrophil phagocytosis by inhibiting complement activation and neutrophil chemotaxis.

The authors used a single-cell assay to examine the chemotactic response of human neutrophils in the presence of S. Typhimurium and S. Typhi. Neutrophils that were in close proximity to S. Typhimurium formed pseudopodia and migrated towards the bacteria, whereas S. Typhi did not elicit a chemotactic response. Chemotaxis was dependent on the complement fragment C5a, which is a neutrophil chemoattractant that is produced following activation of the alternative complement pathway, and addition of a complement inhibitor decreased S. Typhimurium-induced neutrophil migration. These data suggest that S. Typhimurium triggers neutrophil chemotaxis via a complement-dependent mechanism.

Vi polysaccharide capsule inhibits complement-dependent chemotaxis

But how does S. Typhi inhibit neutrophil chemotaxis? The authors compared neutrophil chemotaxis in response to wild-type S. Typhi or a non-capsulated mutant that lacked genes that are involved in the synthesis and export of the Vi polysaccharide capsule. They found that neutrophils extended pseudopodia and migrated towards the non-capsulated mutant but not towards the wild-type strain. Importantly, neutrophil migration towards the non-capsulated mutant strain was inhibited by the addition of a complement inhibitor, which suggests that the Vi polysaccharide capsule inhibits complement-dependent chemotaxis. Consistent with this hypothesis, the authors showed that the chemotactic response to non-capsulated mutants was dependent on C5a and on the surface expression of the phagocytic complement receptor C5aR on neutrophils.

Finally, the authors tested whether the Vi polysaccharide capsule inhibits chemotaxis in vivo. Flow cytometry experiments showed that neutrophils that were recovered from the abdominal cavity of infected mice engulfed significantly more GFP-labelled mutants than wild-type S. Typhi. In addition, neutrophils from C5aR-deficient mice were unable to phagocytose the mutant bacteria. These findings suggest that the S. Typhi Vi capsular polysaccharide prevents complement-dependent clearance in vivo.

In summary, these results show that neutrophil-dependent elimination prevents the dissemination of S. Typhimurium, whereas S. Typhi escapes host defences by inhibiting complement activation and neutrophil chemotaxis. Further work is required to determine whether S. Typhi also uses Vi capsular polysaccharide-independent mechanisms to cause disseminated bacteraemia.