The Capsule Encoding theviaBLocus Reduces Interleukin-17 Expression and Mucosal Innate Responses in the Bovine Intestinal Mucosa during Infection withSalmonella entericaSerotype Typhi

Abstract

The viaB locus contains genes for the biosynthesis and export of the Vi capsular antigen of Salmonella enterica serotype Typhi. Wild-type serotype Typhi induces less CXC chemokine production in tissue culture models than does an isogenic viaB mutant. Here we investigated the in vivo relevance of these observations by determining whether the presence of the viaB region prevents inflammation in two animal models of gastroenteritis. Unlike S. enterica serotype Typhimurium, serotype Typhi or a serotype Typhi viaB mutant did not elicit marked inflammatory changes in the streptomycin-pretreated mouse model. In contrast, infection of bovine ligated ileal loops with a serotype Typhi viaB mutant resulted in more fluid accumulation and higher expression of the chemokine growth-related oncogene alpha (GRO␣) and interleukin-17 (IL-17) than did infection with the serotype Typhi wild type. There was a marked upregulation of IL-17 expression in both the bovine ligated ileal loop model and the streptomycin-pretreated mouse model, suggesting that this cytokine is an important component of the inflammatory response to infection with Salmonella serotypes. Introduction of the cloned viaB region into serotype Typhimurium resulted in a significant reduction of GRO␣ and IL-17 expression and in reduced fluid secretion. Our data support the idea that the viaB region plays a role in reducing intestinal inflammation in vivo.Salmonella enterica serotype Typhi causes a severe systemic infection in humans known as typhoid fever. In contrast, nontyphoidal Salmonella serotypes, such as S. enterica serotype Typhimurium, cause a localized infection in humans manifesting as gastroenteritis (41,64). The different clinical presentations of infections with serotype Typhi and serotype Typhimurium point to important differences during the interaction of these pathogens with their human host. One such difference is the host response elicited in the intestinal mucosa. Gastroenteritis is a typical diarrheal disease characterized by a massive neutrophil influx in the terminal ileum and colon and a predominance of neutrophils in the stool samples of patients (9,17,26). In contrast, typhoid fever is not a typical diarrheal disease, and the intestinal pathology is characterized by a predominantly mononuclear infiltrate (i.e., macrophages and dendritic cells) (17,23,29,30,46).The nature of these differences is poorly understood, partly because the strict adaptation of serotype Typhi to its human host severely limits our ability to study host-pathogen interactions in vivo. While higher primates (i.e., chimpanzees) are susceptible to infections, nonprimate vertebrates and even lower primates (i.e., rhesus macaques) are resistant to serotype Typhi (11). As a result, differences between infections with serotypes Typhi and Typhimurium have mostly been explored with tissue culture models. Although the in vivo relevance of results from tissue culture assays remains to be established in many cases, these studies have revealed marked differences during the interaction...

Molecular insights into farm animal and zoonoticSalmonellainfections

“…Expression of the viaB locus in S. Typhimurium impairs TLRdependent induction of tumour necrosis factor (TNF)-a and IL-6 in murine bone marrow-derived macrophages in vitro as well as TNF-a and inducible nitric oxide synthase production following intraperitoneal infection of mice . Furthermore, Vi expression in S. Typhimurium reduced IL-17 and GROa expression and fluid accumulation in bovine-ligated ileal loops and streptomycinpretreated mice, whereas such responses were improved when an S. Typhi viaB mutant was tested relative to the parent strain (Raffatellu et al 2007). The viaB locus may aid evasion of TLR-mediated detection by a second mechanism, as a regulatory gene encoded in the locus (tviA) can repress the transcription of the master regulators of flagella expression.…”

Simian immunodeficiency virus–induced mucosal interleukin-17 deficiency promotes Salmonella dissemination from the gut

“…Whereas mice normally develop few inflammatory changes in the intestinal mucosa during S. typhimurium infection, pretreatment with streptomycin drastically exacerbates neutrophil influx and inflammation in the cecal mucosa 29 . By using this model, we have previously shown that Il-17 mRNA expression is increased 150-fold in the cecal mucosa of streptomycin-pretreated mice by 48 h after S. typhimurium infection 30 . To assess the importance of IL-17 in controlling S. typhimurium infection, we pretreated two groups of six IL-17 receptor-deficient mice (Il17ra −/− mice) bred on a C57BL/6 background with streptomycin and inoculated them with S. typhimurium or sterile LB broth.…”

“…We streptomycin-pretreated and orally infected groups of eight female C57BL/6 mice or six female Il17ra −/− mice (B6.IL-17R mice, Taconic), aged 8-10 weeks, with S. typhimurium as described previously 30 . At 48 h after infection, we killed the mice and collected the organs for mRNA isolation and bacteriology.…”

“…We inoculated the loops by intralumenal injections of 1 ml of either sterile LB broth or a logarithmically grown culture containing 1 × 10 9 colony-forming units (CFU) of wild-type S. typhimurium (IR715) 30 . We collected loops at 2, 5, or 8 h after inoculation.We streptomycin-pretreated and orally infected groups of eight female C57BL/6 mice or six female Il17ra −/− mice (B6.IL-17R mice, Taconic), aged 8-10 weeks, with S. typhimurium as described previously 30 . At 48 h after infection, we killed the mice and collected the organs for mRNA isolation and bacteriology.…”

Protection from EAE by IL‐4Rα−/− macrophages depends upon T regulatory cell involvement

“…The primers used in these studies are as follow: cyclophilin A, 17 MMP-2, 17 MMP-8, 17 MMP-9, 17 TIMP-2, 17 IFN-g 17 and IL-17. 52 Statistical analysis >Data were analyzed using unpaired or paired Student's t-tests, Mann-Whitney U-test for nonparametric data, one-way analysis of variance (ANOVA) or twoway ANOVA as indicated in the text or figure legends. Pp0.05 was considered significant.…”