Vaccine-induced inflammation and inflammatory monocytes promote CD4+ T cell-dependent immunity against murine salmonellosis.

Prior infection can generate protective immunity against subsequent infection, although the efficacy of such immunity can vary considerably. Live-attenuated vaccines (LAVs) are one of the most effective methods for mimicking this natural process, and analysis of their efficacy has proven instrumental in the identification of protective immune mechanisms. Here, we address the question of what makes a LAV efficacious by characterising immune responses to a LAV, termed TAS2010, which is highly protective (80-90%) against lethal murine salmonellosis, in comparison with a moderately protective (40-50%) LAV, BRD509. Mice vaccinated with TAS2010 developed immunity systemically and were protected against gut-associated virulent infection in a CD4+ T cell-dependent manner. TAS2010-vaccinated mice showed increased activation of Th1 responses compared with their BRD509-vaccinated counterparts, leading to increased Th1 memory populations in both lymphoid and non-lymphoid organs. The optimal development of Th1-driven immunity was closely correlated with the activation of CD11b+Ly6GnegLy6Chi inflammatory monocytes (IMs), the activation of which can be modulated proportionally by bacterial load in vivo. Upon vaccination with the LAV, IMs expressed T cell chemoattractant CXCL9 that attracted CD4+ T cells to the foci of infection, where IMs also served as a potent source of antigen presentation and Th1-promoting cytokine IL-12. The expression of MHC-II in IMs was rapidly upregulated following vaccination and then maintained at an elevated level in immune mice, suggesting IMs may have a role in sustained antigen stimulation. Our findings present a longitudinal analysis of CD4+ T cell development post-vaccination with an intracellular bacterial LAV, and highlight the benefit of inflammation in the development of Th1 immunity. Future studies focusing on the induction of IMs may reveal key strategies for improving vaccine-induced T cell immunity.

CD4+ T cell immunity to Salmonella is transient in the circulation.

While Salmonella enterica is seen as an archetypal facultative intracellular bacterial pathogen where protection is mediated by CD4+ T cells, identifying circulating protective cells has proved very difficult, inhibiting steps to identify key antigen specificities. Exploiting a mouse model of vaccination, we show that the spleens of C57BL/6 mice vaccinated with live-attenuated Salmonella serovar Typhimurium (S. Typhimurium) strains carried a pool of IFN-γ+ CD4+ T cells that could adoptively transfer protection, but only transiently. Circulating Salmonella-reactive CD4+ T cells expressed the liver-homing chemokine receptor CXCR6, accumulated over time in the liver and assumed phenotypic characteristics associated with tissue-associated T cells. Liver memory CD4+ T cells showed TCR selection bias and their accumulation in the liver could be inhibited by blocking CXCL16. These data showed that the circulation of CD4+ T cells mediating immunity to Salmonella is limited to a brief window after which Salmonella-specific CD4+ T cells migrate to peripheral tissues. Our observations highlight the importance of triggering tissue-specific immunity against systemic infections.

Hoodwinking the Big-Eater to Prosper: The Salmonella-Macrophage Paradigm.

Salmonella is a major cause of morbidity and mortality in the developing and underdeveloped nations. Being a foodborne disease, Salmonella infection is primarily contracted through the ingestion of contaminated food or water, or due to close contact with infected/carrier individuals. It is an intracellular pathogen, which can survive and replicate in various cells including macrophages, dendritic cells, epithelial cells, and other white blood cells. Once Salmonella crosses the intestinal barrier, it disseminates to various systemic sites by circulation via immune cells. One of the major cell types which are involved in Salmonella infection are host macrophages. They are the niche for intracellular survival and proliferation of Salmonella and a mode of dissemination to distal systemic sites. These cells are very crucial as they mediate the mounting of an appropriate innate and adaptive anti-Salmonella immune response. In this review, we have tried to concise the current knowledge of complex interactions that occur between Salmonella and macrophages.

Enteropathogens: Tuning Their Gene Expression for Hassle-Free Survival.

Enteropathogenic bacteria have been the cause of the majority of foodborne illnesses. Much of the research has been focused on elucidating the mechanisms by which these pathogens evade the host immune system. One of the ways in which they achieve the successful establishment of a niche in the gut microenvironment and survive is by a chain of elegantly regulated gene expression patterns. Studies have shown that this process is very elaborate and is also regulated by several factors. Pathogens like, enteropathogenic Escherichia coli (EPEC), Salmonella Typhimurium, Shigella flexneri, Yersinia sp. have been seen to employ various regulated gene expression strategies. These include toxin-antitoxin systems, quorum sensing systems, expression controlled by nucleoid-associated proteins (NAPs), several regulons and operons specific to these pathogens. In the following review, we have tried to discuss the common gene regulatory systems of enteropathogenic bacteria as well as pathogen-specific regulatory mechanisms.