| Salmonella spp. pose significant health risks to humans and animals. S. Typhi, the causative agent of typhoid fever, is responsible for 21 million new cases of enteric fever each year and an estimated 200,000 deaths worldwide. Approximately 5-8% of infected individuals will become lifelong bacterial carriers. It is currently unknown why bacteria persist within the host in the face of robust anti-bacterial immune responses. We hypothesize a stalemate between bacterial persistence and the host immune response is determined by anatomical location, and that this dictates CD4 T cell function and infection outcome. Using a mouse model of persistent S. Typhimurium infection, we show lymphoid Salmonella-specific Th1 cells are potent producers of IFN-gamma; and protect mice from challenge when adoptively transferred into naive animals. Conversely, Salmonella-specific CD4 T cells from chronically infected livers exhibit a Tr1-like phenotype, produce large amounts of IL-10, and increase mouse susceptibility to bacterial challenge. These differences in CD4 T cell phenotypes may inhibit macrophage ability to control intracellular bacterial replication; liver Tr1-like cells fail to activate bacterial killing, possibly through the production of IL-10, which reduces the expression of iNOS and nitric oxide production by macrophages. Additionally, we demonstrate liver macrophages from chronically infected mice exhibit an immunosuppressive, M2-like phenotype and are not classically primed to kill intracellular bacteria, unlike macrophages from lymphoid sites. Furthermore, we show that the liver may be responsible for inducing these Tr1-like cells, as liver macrophages are capable of activating and expanding Salmonella -specific CD4 T cells during infection. Thus, we believe the immunosuppressive environment in the liver affords a permissive niche for Salmonella persistence in vivo. However, we believe vaccination can protect mice from Salmonella infection, if potent Th1 cells are induced, as seen in lymphoid tissue during infection. Therefore, we developed a CD4 T cell peptide vaccine against a known Salmonella secreted epitope. We show vaccinated mice generate potent Th1 responses against Salmonella and mice are significantly protected from challenge. These studies provide new insight into the immunological mechanisms regulating bacterial persistence, as well as the role tissue microenvironments play in modulating pathogen-specific immune responses. |
