Salmonella Typhimurium and inflammation: a pathogen-centric affair

Abstract

Microbial infections are controlled by host inflammatory responses that are initiated by innate immune receptors after recognition of conserved microbial products. As inflammation can also lead to disease, tissues that are exposed to microbial products such as the intestinal epithelium are subject to stringent regulatory mechanisms to prevent indiscriminate signalling through innate immune receptors. The enteric pathogen Salmonella enterica subsp. enterica serovar Typhimurium, which requires intestinal inflammation to sustain its replication in the intestinal tract, uses effector proteins of its type III secretion systems to trigger an inflammatory response without the engagement of innate immune receptors. Furthermore, S. Typhimurium uses a different set of effectors to restrict the inflammatory response to preserve host homeostasis. The S. Typhimurium-host interface is a remarkable example of the unique balance that emerges from the co-evolution of a pathogen and its host.

Figure 1.

The type III protein secretion machine encoded by S. Typhimurium within its pathogenicity island 1. (A) Diagram depicting S. Typhimurium delivering effector proteins through its T3SS. (B) Electron micrograph of a S. Typhimurium cells showing multiple T3SS injectisomes (arrows). (C and D) Cryo electron microscopy images of the T3SS machine in situ. A central section (C) and 3-D surface rendering (D) of the T3SS injectisome are shown (adapted from). (E) Cross section of the interface between S. Typhimurium and host cells as revealed by cryo electron tomography (adapted from).

Figure 2.. Model for the interaction of S. Typhimurium with the intestinal epithelium.

After gaining access to the host via the oral route, S. Typhimurium reaches the large intestine where with the help of motility, makes contact with the intestinal epithelium resulting in the activation of the type III secretion system encoded within its pathogenicity island 1 (T3SS-1). Effector proteins delivered by this system trigger cell responses that result in bacterial internalization and the production of pro-inflammatory cytokines. The intracellular environment provides the cues for S. Typhimurium to express another type III protein secretion system encoded within its pathogenicity island 2 (T3SS-2), which allows the pathogen to avoid innate immune defense mechanisms and replicate within cells. The production of pro-inflammatory cytokines by the infected cells starts a cascade of events that lead to the recruitment of inflammatory cells. The tissue inflammatory response alters the intestinal lumen environment resulting the depletion of the resident microbiota and the availability of nutrients and electron acceptors that fuel the replication of the luminal population of S. Typhimurium.

Figure 3.. Model for the S. Typhimurium pro- and anti-inflammatory signaling in the intestinal tract through its type III secretion effectors.

Pro- and anti-inflammatory signaling pathways are depicted in red and green, respectively. The effector proteins and their place of action are noted.