Salmonella-host interactions - modulation of the host innate immune system

Abstract

Salmonella enterica (S. enterica) are Gram-negative bacteria that can invade a broad range of hosts causing both acute and chronic infections. This phenotype is related to its ability to replicate and persist within non-phagocytic host epithelial cells as well as phagocytic dendritic cells and macrophages of the innate immune system. Infection with S. enterica manifests itself through a broad range of clinical symptoms and can result in asymptomatic carriage, gastroenteritis, systemic disease such as typhoid fever and in severe cases, death (1). Exposure to S. enterica serovars Typhi and Paratyphi exhibits clinical symptoms including diarrhea, fatigue, fever, and temperature fluctuations. Other serovars such as the non-typhoidal Salmonella (NTS), of which there are over 2,500, are commonly contracted as, but not limited to, food-borne sources causing gastrointestinal symptoms, which include diarrhea and vomiting. The availability of complete genome sequences for many S. enterica serovars has facilitated research into the genetic determinants of virulence for this pathogen. This work has led to the identification of important bacterial components, including flagella, type III secretion systems, lipopolysaccharides, and Salmonella pathogenicity islands, all of which support the intracellular life cycle of S. enterica. Studies focusing on the host-pathogen interaction have provided insights into receptor activation of the innate immune system. Therefore, characterizing the host-S. enterica interaction is critical to understand the pathogenicity of the bacteria in a clinically relevant context. This review outlines salmonellosis and the clinical manifestations between typhoidal and NTS infections as well as discussing the host immune response to infection and the models that are being used to elucidate the mechanisms involved in Salmonella pathogenicity.

Keywords: NTS; gastroenteritis; host innate immunity; macrophages; pathogenicity islands; salmonellosis.

Figure 1

Classification of Salmonella species and subspecies.

Figure 2

Schematic illustration of the genes of SPI-1 and SPI-2 indicating their functional categories is shown. In Salmonella, SPI-1 and SPI-2 encode a range of effector proteins, secretion apparatus, and transcriptional regulators in addition to T3SS-1 and T3SS-2.

Figure 3

Schematic illustration of the infection of epithelial cells of the lower intestine and macrophages by Salmonella is shown. (A) The complex membrane structure of Salmonella allows it to survive until reaching the epithelial cell wall of the host in the lower intestine. (B) Salmonella then translocate across M cells of Peyer’s patches or actively invade epithelial cells by the secretion of effector proteins through the SPI-1 encoded T3SS-1. (C) (i) After crossing the epithelial barrier, Salmonella are engulfed by proximal macrophages that will secrete effector proteins into the cytosol of the cell via the SPI-2 encoded T3SS-2 and prevent fusion of the phagosome with the lysosome. (ii) Within the SCV, Salmonella will proliferate resulting in cytokine secretion by the macrophage. (iii) Finally, the macrophage will undergo apoptosis, and Salmonella will escape the cell to basolaterally reinvade epithelial cells or other phagocytic cells of the host innate immune system.