SalmonellaPersistence and Host Immunity Are Dictated by the Anatomical Microenvironment

Abstract

The intracellular bacterial pathogen Salmonella is able to evade the immune system and persist within the host. In some cases, these persistent infections are asymptomatic for long periods and represent a significant public health hazard as potential chronic carriers, yet the mechanisms that control persistence are incompletely understood. Using a mouse model of chronic typhoid fever combined with MHC class II tetramers to interrogate endogenous, Salmonella-specific CD4+ helper T cells, we show certain host microenvironments may favorably contribute to a pathogen's ability to persist in vivo. We demonstrate that the environment in the hepatobiliary system may contribute to the persistence of Salmonella Typhimurium through liver resident immunoregulatory CD4+ helper T cells, alternatively activated macrophages, and impaired bactericidal activity. This contrasts with lymphoid organs, such as the spleen and mesenteric lymph nodes, where these same cells appear to have a greater capacity for bacterial killing, which may contribute to control of bacteria in these organs. We also find that, following an extended period of infection of greater than two years, the liver appeared to be the only site that harbored Salmonella. This work establishes a potential role for non-lymphoid organ immunity in regulating chronic bacterial infections and provides further evidence for the hepatobiliary system as the site of chronic Salmonella infection.