Salmonella enterica serovar Typhimurium skills to succeed in the host: virulence and regulation

Abstract

Salmonella enterica serovar Typhimurium is a primary enteric pathogen infecting both humans and animals. Infection begins with the ingestion of contaminated food or water so that salmonellae reach the intestinal epithelium and trigger gastrointestinal disease. In some patients the infection spreads upon invasion of the intestinal epithelium, internalization within phagocytes, and subsequent dissemination. In that case, antimicrobial therapy, based on fluoroquinolones and expanded-spectrum cephalosporins as the current drugs of choice, is indicated. To accomplish the pathogenic process, the Salmonella chromosome comprises several virulence mechanisms. The most important virulence genes are those located within the so-called Salmonella pathogenicity islands (SPIs). Thus far, five SPIs have been reported to have a major contribution to pathogenesis. Nonetheless, further virulence traits, such as the pSLT virulence plasmid, adhesins, flagella, and biofilm-related proteins, also contribute to success within the host. Several regulatory mechanisms which synchronize all these elements in order to guarantee bacterial survival have been described. These mechanisms govern the transitions from the different pathogenic stages and drive the pathogen to achieve maximal efficiency inside the host. This review focuses primarily on the virulence armamentarium of this pathogen and the extremely complicated regulatory network controlling its success.

Fig 1

Pathogenesis model of Salmonella enterica serovar Typhimurium. 1, Salmonella cells attach to the intestinal epithelium by means of adhesins, such as those encoded within SPI-3 and SPI-4. 2 and 3, Invasion of bacteria follows, and engulfment is mediated by virulence factors encoded within SPI-1 and SPI-5. 4, Alternatively, bacterial cells can also be directly taken up by dendritic cells from the submucosa. 5, Once inside the cytoplasm, Salmonella is localized within the SCV, where it replicates. Factors encoded within SPI-2 and the pSLT plasmid are essential for survival. 6, The SCVs transcytose to the basolateral membrane and release the internal cells to the submucosa. 7, Bacteria are internalized within phagocytes and located again within an SCV, where SPI-3, in addition to SPI-2 and the pSLT plasmid, play an important role. Lastly, these infected phagocytes can disseminate through the lymph and the bloodstream. (Modified from reference with permission from the BMJ Publishing Group.)

Fig 2

Schematic representation of the genes carried within the five SPIs and their putative functions.

Fig 3

SPI-1 regulatory network. Blue arrows indicate activation or autoactivation, whereas red blunt-end arrows indicate repression or autorepression. Discontinuous arrows suggest the putative regulatory target proposed in this model. Regulators in yellow are those encoded within SPI-1 (with the exception of RtsA) that play a critical role in the regulation of the invasion phenotype. Green refers to NAPs, whereas light orange is used for 2CRSs. The positive regulatory interactions between HilD, HilC, and RtsA have been omitted to avoid complicating the figure. The putative direct activation of HilA by SirA has not been included in this model due to lack of corroborative data. IHF activation is deduced to be mediated through HilD as for Fis and HU according to the information provided in the text. The PhoQ-PhoP repressive effect on the prg genes is proposed to occur through repression of HilA by means of posttranscriptional repression of HilD, since no direct effect has been reported in these SPI-1 genes. According to this model, all the 2CRSs exert their effect through HilD, with the exception of QseC-QseB, which is currently known to affect only InvF. For this reason, we have used a discontinuous arrow despite the possibility that it may also be acting at the level of HilD. Moreover, most of the regulatory signals are integrated at the level of HilD, mainly by posttranscriptional modulation, which heads the hierarchy of the SPI-1-encoded regulators.

Fig 4

Cross talk between all the SPIs. The regulatory effects which may be explained through an indirect pathway have not been represented to make comprehension easier (i.e., the effects that HilD, HilC, HilE, PhoQ-PhoP, and SirA-BarA exert on either SPI-4 or SPI-5). According to the evidence reported in the text, the regulators marked with an asterisk are those proposed to act in this model on the SPI-2 genes via SsrA-SsrB. The roles reported for Lon and DnaK regarding systemic virulence have not been included in this model, since there is no specific information about their target genes. (A) Regulators positively influencing expression of the SPI genes. (B) Regulators leading to a repressor effect.

Fig 5

Cross talk between the virulence elements. The reported effects of SirA and CsrA on flagellar genes are not considered in this scheme, since no direct evidence of independent HilA activity have been presented. The regulatory effects that flagellar genes exert on SPI-1 and type I fimbriae are mediated by FliZ, whereas SPI-1 repression of flagellar genes is dependent on HilA activity. The influence of biofilm on SPI-1 expression is mediated by CsgD.