Mechanism of capsule-mediated innate immune evasion by Salmonella enterica serotype Typhi

The viaB locus enables Salmonella enterica serotype Typhi to reduce Toll-like receptor (TLR) dependent cytokine production in tissue culture models. This DNA region contains genes involved in the regulation (tviA), biosynthesis (tviBCDE) and export (vexABCDE) of the Vi capsule. Here, we show that expression of the Vi capsule in S. Typhimurium but not expression of the TviA regulatory protein prevents both in vitro and in vivo recognition of S. Typhimurium's lipopolysaccharide (LPS) by TLR4. Interestingly, comparing S. Typhi to an isogenic non-capsulated mutant (DeltatviBCDEvexABCDE mutant) revealed that the Vi antigen interfered with complement component 3 (C3) deposition on the bacterial cell surface. Decreased complement fixation resulted in reduced bacterial binding to complement receptor (CR) 3 on the surface of macrophages in vitro and decreased CR3-dependent clearance of capsulated S. Typhi from the liver and spleen of mice. Furthermore, a CR3-dependent attenuation of cytokine responses in mice was observed when the Vi capsular polysaccharide was expressed in S. Typhimurium, which suggests that the Vi capsular polysaccharide reduces cytokine responses in vivo by interfering with the function of CR3. Consistent with this idea, inhibition of CR3 binding to LPS is required for full activation of TLR4-dependent responses. This mechanism is likely relevant to other bacterial pathogens, which prevent CR3 mediated phagocytosis using a capsular polysaccharide.