Life in the inflamed intestine, Salmonella style

Abstract

The lower gastrointestinal tract is densely populated with resident microbial communities (microbiota), which do not elicit overt host responses but rather provide benefit to the host, including niche protection from pathogens. However, introduction of bacteria into the underlying tissue evokes acute inflammation. Non-typhoidal Salmonella serotypes (NTS) elicit this stereotypic host response by actively penetrating the intestinal epithelium and surviving in tissue macrophages. Initial responses generated by bacterial host cell interaction are amplified in tissue through the interleukin (IL)-18/interferon-gamma and IL-23/IL-17 axes, resulting in the activation of mucosal barrier functions against NTS dissemination. However, the pathogen is adapted to survive antimicrobial defenses encountered in the lumen of the inflamed intestine. This strategy enables NTS to exploit inflammation to outcompete the intestinal microbiota, and promotes the Salmonella transmission by the fecal/oral route.

Figure 1

The inflammation-adapted pathogenic lifestyle of S. Typhimurium. The schematic shows host factors (in red) and bacterial factors (in blue) contributing to the development of acute intestinal inflammation within hours after S. Typhimurium infection of the intestinal mucosa. The bacterium initiates intestinal inflammation through direct interaction with host cells, resulting in a release of cytokines, such as IL-18 and IL-23. The cytokines IL-18 and IL-23 help to amplify responses in tissue by stimulating T cells to produce IFN-γ (which activates macrophage antimicrobial activities), IL-17 (which orchestrates neutrophil barrier function) and IL-22 (which stimulates epithelial antimicrobial responses). The ability to grow on mucus carbohydrates and its resistance against antimicrobials (e.g. lipocalin-2 resistance mediated by the iroBCDEN genes) enable S. Typhimurium to benefit from the changes encountered in the inflamed intestine, resulting in its luminal outgrowth and enhanced transmission. Although intracellular salmonellae might lack flagellae in certain host tissues or cell types, in vivo analysis of flagellin expression suggests that intracellular bacteria isolated from intestinal tissue contain these surface structures . Abbreviations: CD8, CD8⁺ αβ T cell; DC, dendritic cell; MO, macrophage; NK, natural killer cell; NKT, natural killer T cell; PAMPs, pathogen associated molecular patterns; PMN, neutrophil; δγ TC, δγ T cell; Th1, CD4⁺ αβ memory type-1 T-helper cell; Th17, CD4⁺ αβ memory type-17 T-helper cell.

Figure 2

Two distinct S. Typhimurium populations are present in the intestine. Detection of the S. Typhimurium O-antigen by immunohistochemistry (streptavidin-biotin-peroxidase, brown precipitate) in a section of the ileal mucosa from a rhesus macaque ligated ileal loop, 5 hours after infection. The image shows the coexistence of two distinct S. Typhimurium populations, one invading intestinal tissue thereby triggering inflammation (arrow), the other benefiting from the resulting environmental changes in the luminal mucus layer (arrow head). The section was counterstained with hematoxylin (blue color). Scale bar = 100 µm.