Innate immune response to Salmonella typhimurium, a model enteric pathogen

Abstract

The innate immune system provides the first line of defense against invading microorganisms by inducing a variety of inflammatory and antimicrobial responses. These responses are particularly important in the gastrointestinal tract, where the needs for efficient nutrient uptake and host defense collide. Many pathogens have evolved to specifically colonize the intestine, causing millions of cases of enteric infections a year. A paradigm of an enteric pathogen is Salmonella enterica, a gram-negative bacterium that causes a wide range of gastrointestinal and systemic diseases. Infections with Salmonella enterica serovar Typhimurium (S. typhimurium) lead to an acute intestinal inflammation in human and animal hosts, as a result of the bacterium invading the mucosa. A distinctive feature of Salmonella is that it has not only adapted to survive in a strong inflammatory environment, but it also uses this adaptation as a strategy to gain a growth advantage over the intestinal microbiota. We will use the model organism S. typhimurium to discuss the innate immune mechanisms employed by the mammalian gastrointestinal system and how the pathogen responds and subverts these mechanisms. In particular, we focus on the recognition of extra- and intra-cellular Salmonellae by germline-encoded pattern recognition receptors of the TLR and NLR families, and how Salmonella might profit from the activation of these receptors.

Figure 1. Schematic representation showing the different routes Salmonella can take in order to invade the intestinal mucosa. (1) The major pathway of invasion is through M cell mediated transcytosis at the Peyer’s patches. (2) An alternative route is via uptake by enterocytes. (3) This route requires the injection of bacterial effector proteins by the SPI-1 Type 3 Secretion System that induce ruffling and uptake of the bacterium. Uptake through intercalating CX3CR1⁺ macrophages/DCs might represent an additional route of invasion.

Figure 2. The gastric innate immune response to Salmonella. (A) Following the invasion of the mucosa, the presence of Salmonella is detected by pattern recognition receptors. Extracellular Salmonella are detected by Toll-like receptors inducing a transcriptional response leading to the expression of pro-inflammatory cytokines such as IL-23. Intracellular Salmonella activate NOD-like receptors that can induce IL-23 expression, as well as the assembly of NLRC4/NLRP3 inflammasomes that activate Caspase-1, promoting the secretion of mature IL-1β and IL-18. SPI-1 mediated activation of Caspase-1 in epithelial cells might contribute to IL-18 secretion. (B) IL-18 and IL-23 amplify the inflammatory response by paracrine signaling. IL-18 induces the release of IFNγ from T cells, while IL-23 induces the release of IL-22 and IL-17. These cytokines induce the increased production of mucins and antimicrobial peptides, and promote the release of CXC chemokines leading to an influx of neutrophils into the mucosa. (C) Infiltrating neutrophils are crucial for the killing of extracellular Salmonellae. Although considered an intracellular pathogen, Salmonella can be found extracellularly following transcytosis through M cells or after pyroptosis induced host cell lysis. Besides clearing the pathogen, neutrophil influx can also lead to damage to intestinal tissue, resulting in the loss of epithelial cell barrier function and promoting diarrhea.