Typhoid fever: "you can't hit what you can't see"

Abstract

The host restricts dissemination of invasive enteric pathogens, such as non-typhoidal Salmonella serovars, by mounting acute inflammatory responses characterized by the recruitment of neutrophils. However, some enteric pathogens, such as Salmonella enterica serovar Typhi (S. typhi), can bypass these defenses and cause an invasive bloodstream infection known as typhoid fever. Recent studies on virulence mechanisms of S. typhi suggest that tight regulation of virulence gene expression during the transition from the intestinal lumen into the intestinal mucosa enables this pathogen to evade detection by the innate immune system, thereby penetrating defenses that prevent bacterial dissemination. This example illustrates how the outcome of host pathogen interaction at the intestinal mucosal interface can alter the clinical presentation and dictate the disease outcome.

Figure 1. Detection of S. typhimurium by the innate immune system results in neutrophil recruitment. Complement, TLR5 and TLR4/MD2/CD14 detect conserved molecular patterns of S. typhimurium, including LPS and flagella. A pathogen-induced process detected by the host innate immune system is the deployment of T3SS-1, which is sensed through NLRC4. Signals generated by activation of complement, TLR5, TLR4/MD2/CD14 and NLRC4 cooperate in orchestrating neutrophil recruitment.

Figure 2. TviA-mediated gene regulation conceals conserved molecular patterns and pathogen-induced processes during S. typhi infection. Expression of TviA is induced at tissue osmolarity by the OmpR/EnvZ two-component system. TviA in conjunction with RcsB activates expression of the tviBCDEvexABCDE operon and represses expression of the flhDC operon. As a result, S. typhi expresses the Vi-antigen while suppressing flagella and T3SS-1 expression when entering the intestinal mucosa. The Vi-antigen interferes with the detection of LPS as a conserved molecular pattern. Thus, TviA-mediated gene regulation prevents detection of a pathogen-induced process (i.e., the deployment of T3SS-1) and detection of conserved molecular patterns (i.e., LPS and flagella) by the innate immune surveillance system in the intestinal mucosa.