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

REVIEW published: 29 September 2017 doi: 10.3389/fcimb.2017.00428 Evolution of Salmonella-Host Cell Interactions through a Dynamic Bacterial Genome Bushra Ilyas 1, 2 , Caressa N. Tsai 1, 2 and Brian K. Coombes 2* 1 Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, Canada, 2 Michael DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, ON, Canada Edited by: Ariel Blocker, University of Bristol, United Kingdom Reviewed by: Andres Vazquez-Torres, University of Colorado Denver, United States Jose L. Puente, National Autonomous University of Mexico, Mexico *Correspondence: Brian K. Coombes Received: 21 June 2017 Accepted: 19 September 2017 Published: 29 September 2017 Citation: Ilyas B, Tsai CN and Coombes BK (2017) Evolution of Salmonella-Host Cell Interactions through a Dynamic Bacterial Genome. Front. Cell. Infect. Microbiol. 7:428. doi: 10.3389/fcimb.2017.00428 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, horizontal gene transfer, regulatory evolution, virulence regulation, gene loss, comparative genomics, xenogeneic silencing INTRODUCTION Salmonella is a genus of enteric pathogens that consists of two species, Salmonella enterica and Salmonella bongori, which can cause disease in a broad range of hosts. S. bongori is predominantly associated with infection in reptiles, although it has been isolated in human infections (Nastasi et al., 1988; Giammanco et al., 2002). S. enterica is further divided into seven subspecies, which can cause gastroenteritis or systemic disease in a variety of warm- and cold-blooded animals (McQuiston et al., 2008). Among the S. enterica subspecies, S. enterica subsp. enterica is the only one that can infect mammals, and is associated with human disease. This subspecies includes host-restricted serovars like Salmonella Typhi, which causes typhoid fever in humans, and the broad host-range Salmonella Typhimurium, which causes gastroenteritis in humans and other mammals (Uzzau et al., 2000). The evolution of Salmonella as a pathogen has been broadly studied over the past few decades. The recent rise in comparative genomics methods has cast a light on the molecular basis of pathogenesis, revealing that the evolution of Salmonella toward pathogenicity was mediated by several horizontal transfer events (Bäumler, 1997; Groisman and Ochman, 1997). Frontiers in Cellular and Infection Microbiology | www.frontiersin.org 1 September 2017 | Volume 7 | Article 428 Ilyas et al. Genomic Basis of Salmonella Pathogenesis Genes acquired by horizontal transfer can confer new phenotypes to the recipient bacteria and are often the source of adaptive changes that maximize fitness in a given niche (Ochman et al., 2000). In the Salmonella genomics vernacular, horizontally acquired multi-gene loci linked to infection are called Salmonella Pathogenicity Islands (SPIs), and have been described as the “molecular toolbox” for Salmonella pathogenesis (Gal-Mor and Finlay, 2006). The SPI pan-genome includes 21 SPIs, most of which are present in both species, and across all subspecies (McClelland et al., 2001). However, there is genetic flux with the Salmonella species and subspecies, which define host range and disease phenotype (Bäumler, 1997; Fookes et al., 2011). Perhaps the best-studied serovar of Salmonella is S. enterica subsp. enterica sv. Typhimurium (S. Typhimurium). S. Typhimurium is amenable to molecular manipulation, can infect numerous cell types, and robust animal models have been developed to model both self-limiting gastroenteritis and systemic infection (Finlay and Brumell, 2000; Tsolis et al., 2011). Together, these tools have laid the foundation for understanding the genetic basis for Salmonella virulence, and have helped understand the host response to infection. The contributions of SPI-1 and 2 to Salmonella pathogenicity have been reviewed in detail several times (Hensel, 2000; Wallis and Galyov, 2000; Waterman and Holden, 2003; Haraga et al., 2008), and more recent attention has been directed toward the evolution and virulence determinants of the other SPIs (Morgan et al., 2004; Haneda et al., 2009; Nieto et al., 2016). In this review, we highlight the contribution of horizontally acquired genes to the adaptation of Salmonella as a pathogen and its biology within host cells. Further, because many bacteria share a conserved repertoire of core genes, we discuss a notion that uncovering selective changes to gene deployment via regulatory evolution among conserved genes is a strategy to uncover novel aspects of infection biology. DISTINCT VIRULENCE FACTORS DRIVE SPECIFIC STAGES OF SALMONELLA INFECTION Genetically susceptible mice (Nramp/SLC11A1−/− ) orally infected with S. Typhimurium develop systemic disease, characterized by high bacterial burdens in the spleen and liver, gross intestinal pathology, and death from systemic bacteremia (Santos et al., 2001; Cuellar-Mata et al., 2002). Streptomycin pretreatment in this model lowers intrinsic colonization resistance and intensifies the bacterial-driven intestinal inflammation, a finding that has been extensively leveraged to understand how Salmonella competes metabolically in the inflamed intestine (Barthel et al., 2003; Winter et al., 2010a,b). During the infection process, S. Typhimurium invades epithelial cells or is taken up by M cells, colonizes the Peyer’s patches and associated lymphoid tissue, and invades or is phagocytosed by immune cells such as macrophages and neutrophils. In this permissive niche for replication, systemic disse (...truncated)