Host restriction, pathogenesis and chronic carriage of typhoidal Salmonella

Abstract

While conjugate vaccines against typhoid fever have recently been recommended by the World Health Organization for deployment, the lack of a vaccine against paratyphoid, multidrug resistance and chronic carriage all present challenges for the elimination of enteric fever. In the past decade, the development of in vitro and human challenge models has resulted in major advances in our understanding of enteric fever pathogenesis. In this review, we summarise these advances, outlining mechanisms of host restriction, intestinal invasion, interactions with innate immunity and chronic carriage, and discuss how this knowledge may progress future vaccines and antimicrobials.

Keywords: Salmonella Paratyphi A; Salmonella Typhi; bacterial pathogenesis; enteric fever; enteric infection; typhoid.

Figure 1.

Hypothesised mechanisms of host restriction. (A)Salmonella Typhi fimbriae are specific for adhesion to human epithelial cells, while S. Typhimurium fimbriae can adhere to cells from a variety of hosts. (B)Salmonella Typhimurium produces bacterial effector GtgE that cleaves Rab32, preventing killing in mouse macrophages. Salmonella Typhi lacks GtgE and is therefore killed in mouse macrophages. (C)Salmonella Typhi is more susceptible to iron starvation than S. Typhimurium in vitro and in mice, and therefore is only able to infect iron-overloaded mice. (D) The typhoid toxin is secreted by intracellular bacteria into the Salmonella-containing vacuole and transported to the extracellular space. Here, it binds to target cell receptors (PODXL on epithelial cells, CD45 on macrophages and T and B cells; Galán 2016). The toxin preferentially binds to glycans terminated by Neu5Ac, characteristic of human cells. In the nucleus of target cells, the DNase activity of the toxin causes DNA damage and cell cycle arrest.

Figure 2.

Invasion of the intestinal epithelium by S. Typhi. Salmonella Typhi invasion is impeded by mucus and the glycocalyx acting as physical barriers, as well as the action of defensins, cathelicidins and IgA in the intestinal mucosa. Those bacteria that successfully adhere to the epithelium using fimbriae cross by T3SS-1- or STIV-mediated invasion of intestinal epithelial cells. Bacteria in the lamina propria and subepithelial dome (SED) are then phagocytosed and systemically disseminated to the liver and spleen via the blood and lymph.

Figure 3.

Genetic regulation in response to changes in osmolarity. In the high osmolarity intestinal lumen, EnvZ auto-phosphorylation activity is high, ultimately resulting in the phosphorylation of OmpR and suppression of the viaB locus. Thus, Vi capsule biosynthesis is supressed, while T3SS-1 and flagellin expression can take place. In the lower osmolarity environment inside cells, EnvZ undergoes a conformational change that reduces auto-phosphorylation. The viaB locus is hence expressed, resulting in synthesis of TviA and the Vi capsule. Regulatory protein TviA then goes on to supress T3SS1 and flagellin expression. Under high osmolarity conditions, SPI-9 is also transcribed by a mechanism dependent on rpoS.

Figure 4.

Complement evasion by S. Typhi and S. Paratyphi A. The alternative and classical complement pathways culminate in the formation of C3 and C5 convertases, resulting in the attraction of neutrophils by C5a and opsonisation by C3b. In S. Typhi expression of the Vi capsule and absence of very long O-antigen chains prevents C3b and IgM deposition, while in S. Paratyphi A the production of very long modified O-antigens prevents IgM binding shorter O-antigen chains on its surface. Furthermore, the surface protease PgtE cleaves C3b, C4b and B.

Figure 5.

Chronic carriage of S. Typhi in the gallbladder. Bile induces S. Typhi to upregulate SPI-1 genes, resulting in invasion of the gallbladder epithelium. Flagellin allows S. Typhi to bind to gallstones and forms a scaffold to which further bacteria can bind. The extracellular matrix consists of curli fimbriae, Vi antigen, O-antigen and extracellular DNA.