The Vi-capsule prevents Toll-like receptor 4 recognition of Salmonella

Abstract

SummaryThe 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. Expression of the Vi capsule in S. Typhimurium, but not expression of the TviA regulatory protein, reduced tumour necrosis factor-alpha (TNF-a) and IL-6 production by murine bone-marrow derived macrophages. Production of TNF-a and IL-6 was dependent on expression of TLR4 as stimulation of macrophages from TLR4 -/-mice with S. Typhimurium did not result in expression of these cytokines. Intraperitoneal infection of mice with S. Typhimurium induced expression of TNF-a and inducible nitric oxide synthase (iNOS) in the liver. Introduction of the cloned viaB region into S. Typhimurium reduced TNF-a and iNOS expression to levels observed after infection with a S. Typhimurium msbB mutant. In contrast, no differences in TNF-a expression between the S. Typhimurium wild type and strains expressing the Vi-capsule or carrying a mutation in msbB were observed after infection of TLR4 -/-mice. We conclude that the Vi capsule prevents both in vitro and in vivo recognition of S. Typhimurium lipopolysaccharide by TLR4.

Host Specificity of Bacterial Pathogens

“…However, S. Typhi does not elicit overt host responses during the initial invasion of the intestinal mucosa, as indicated by a 2-wk incubation period of typhoid fever . S. Typhi avoids the generation of responses during the initial phase of infection because it evades innate immunity by expressing a capsular polysaccharide (Raffatellu et al 2005;Wilson et al 2008;Haneda et al 2009) and by rapidly repressing expression of flagella and T3SS-1 during the transition through the epithelial lining (Winter et al 2010b). These mechanisms enable S. Typhi to slip past the host's defenses to cause an invasive bloodstream infection.…”

Genetic determinants of immune-response to a polysaccharide vaccine for typhoid

“…Downregulation of TLR-mediated immune responses through diminished TLR-mediated cell signaling or expression is an important immune evasion mechanism in some bacterial pathogens (Alvarez 2005;Babu et al 2009). Data from experiments with human colonic tissue explants indicate that the Vi antigen reduces TLR-mediated IL-8 signaling, thereby evading TLR-mediated host response triggering neutrophil infiltration in the intestinal mucosa (Wilson et al 2008). However, it is not clear if Vi polysaccharide is recognized by TLR1 or if the TLR1 gene influences host responses to co-infections that then indirectly influences host response to vaccination with Vi PS.…”

Salmonella: Invasion, Evasion & Persistence

“…Endotoxic shock is characterised by a decrease in hypotension and microvascular thrombosis as the result of fibrin deposition in capillaries (Waage et al, 1991). LPS is thought to contribute to septic shock and mortality in patients with non-typhoidal Salmonella, in part due to the rapid production of TLR4-dependant TNFin macrophages (Engelberts et al, 1991;Wilson et al, 2008). The synergic induction of nitric oxide synthase, by TNF-, IFN-and IL-1 , increases production of nitric oxide which is a powerful vasodilator contributing to hypotension (Petros et al, 1991).…”