Evolution of Salmonella-Host Cell Interactions through a Dynamic Bacterial Genome

Abstract

Salmonella Typhimurium has a broad arsenal of genes that are tightly regulated and coordinated to facilitate adaptation to the various host environments it colonizes. The genome of Salmonella Typhimurium has undergone multiple gene acquisition events and has accrued changes in non-coding DNA that have undergone selection by regulatory evolution. Together, at least 17 horizontally acquired pathogenicity islands (SPIs), prophage-associated genes, and changes in core genome regulation contribute to the virulence program of Salmonella. Here, we review the latest understanding of these elements and their contributions to pathogenesis, emphasizing the regulatory circuitry that controls niche-specific gene expression. In addition to an overview of the importance of SPI-1 and SPI-2 to host invasion and colonization, we describe the recently characterized contributions of other SPIs, including the antibacterial activity of SPI-6 and adhesion and invasion mediated by SPI-4. We further discuss how these fitness traits have been integrated into the regulatory circuitry of the bacterial cell through cis-regulatory evolution and by a careful balance of silencing and counter-silencing by regulatory proteins. Detailed understanding of regulatory evolution within Salmonella is uncovering novel aspects of infection biology that relate to host-pathogen interactions and evasion of host immunity.

Keywords: Salmonella infection biology; bacterial pathogenesis; comparative genomics; gene loss; horizontal gene transfer; regulatory evolution; virulence regulation; xenogeneic silencing.

Figure 1

The course of Salmonella infection within the intestine is driven by horizontally acquired virulence factors. Genes encoded on the horizontally acquired Salmonella Pathogenicity Islands (SPIs) and prophage associated genes are important during Salmonella infection of the intestine. Salmonella colonizes the intestinal lumen through activation of robust inflammation by genes encoded on the sopE prophage, and SPI-1 secreted effectors, and outcompetes commensal microbes metabolically, and with a type 6 secretion system encoded on SPI-6. The PhoPQ and PmrAB two-component systems regulate resistance to luminal antimicrobial peptides. Surface proteins encoded on SPI-3 and SPI-4 drive attachment to epithelial cells, and bacterial mediated endocytosis into epithelial cells is induced by gene products from SPI-1 and SPI-5. Modification of the bacterial endosome and survival within the Salmonella containing vacuole (SCV) is driven by SPI-1 and the Gifsy-1 prophage. Within the SCV and in immune cells like neutrophils and macrophages, resistance to immune responses such as oxidative stress is mediated by the Gifsy-2 and Fels-1 prophages, and SPI-11, SPI-12, and SPI-16 that remodel the outer membrane to evade immune responses. Survival within macrophages is mediated by SPI-2, SPI-5, SPI-13. Together, these genes allow for colonization and systemic infection of Salmonella Typhimurium.

Figure 2

Development of novel regulatory pathways through transcriptional rewiring. (A) Horizontally acquired genes in Salmonella are silenced by H-NS, and cis-regulatory elements can undergo mutations to acquire binding sites that bring these genes under the control of a core virulence regulator such as PhoP. This counter-silencing allows for activation of virulence relevant horizontally acquired genes like pagC in infection relevant conditions. (B) Acquisition of the transcriptional regulator SsrB in Salmonella Typhimurium led to cis-regulatory evolution of core genes that allow them to come under the regulatory control of SsrB. This regulatory rewiring of core genes fine-tunes their expression under infection conditions with other SsrB regulated genes.