Salmonella Populations inside Host Cells

Abstract

Bacteria of the Salmonella genus cause diseases ranging from gastroenteritis to life-threatening typhoid fever and are among the most successful intracellular pathogens known. After the invasion of the eukaryotic cell, Salmonella exhibits contrasting lifestyles with different replication rates and subcellular locations. Although Salmonella hyper-replicates in the cytosol of certain host cell types, most invading bacteria remain within vacuoles in which the pathogen proliferates at moderate rates or persists in a dormant-like state. Remarkably, these cytosolic and intra-vacuolar intracellular lifestyles are not mutually exclusive and can co-exist in the same infected host cell. The mechanisms that direct the invading bacterium to follow the cytosolic or intra-vacuolar "pathway" remain poorly understood. In vitro studies show predominance of either the cytosolic or the intra-vacuolar population depending on the host cell type invaded by the pathogen. The host and pathogen factors controlling phagosomal membrane integrity and, as consequence, the egress into the cytosol, are intensively investigated. Other aspects of major interest are the host defenses that may affect differentially the cytosolic and intra-vacuolar populations and the strategies used by the pathogen to circumvent these attacks. Here, we summarize current knowledge about these Salmonella intracellular subpopulations and discuss how they emerge during the interaction of this pathogen with the eukaryotic cell.

Keywords: Salmonella; cytosol; heterogeneity; intracellular; vacuole.

Figure 1

Main milestones in the discovery and subsequent characterization of the Salmonella-containing vacuole (SCV), the cytosolic population and the contribution of host and pathogen factors to the dynamics of the intra-vacuolar and cytosolic populations.

Figure 2

Salmonella intracellular populations reported in epithelial cells, fibroblasts and macrophages. A comparison of the data obtained in vivo and in vitro is also depicted. Abbreviations: NAIP1-6, neural apoptosis inhibitory proteins 1-6; NLRC4, NLR family CARD domain-containing protein 4; RNS, reactive nitrogen species; ROS, reactive oxygen species; SCV, Salmonella-containing vacuole; SIF, Salmonella-induced filaments; T1, SPI1-encoded type III secretion system; T2, SPI2-encoded type III secretion system.

Figure 3

Different stages and main regulatory factors (host and pathogen origin) modulating the generation of the cytosolic and intra-vacuolar Salmonella populations. (A) Steps influencing the generation of cytosolic and intra-vacuolar populations. The factors involved are indicated. Those cases in which the effect is inhibitory are highlighted in gray; (B) Scheme depicting the main stages characterized in various host cell types (epithelial cell, fibroblasts, macrophages) regarding the generation of distinct bacterial populations as the infection progresses overtime. Factors known to contribute to defined steps are indicated. Abbreviations: AMPK, AMP-activated protein kinase; ATG5, autophagy protein 5; COPII, coat protein complex-2; Gal3, galectin-3; GBPs, guanylate-binding proteins; HOPS, homotypic fusion and vacuole sorting complex; Hsc73, heat shock cognate protein 73; LAMP-2A, receptor for chaperone-mediated autophagy; LC3, microtubule-associated proteins 1A/1B light chain 3B; MTMR4, myotubularin-4; mTOR, mammalian target of rapamycin; PLEKHM1, Pleckstrin homology domain-containing protein family member 1; P-L fusion, phagosome-lysosome fusion; RNS, reactive nitrogen species; ROS, reactive oxygen species; SCV, Salmonella-containing vacuole; SIF, Salmonella-induced filaments; T1, SPI1-encoded type III secretion system; T2, SPI2-encoded type III secretion system; VAMP7, vesicle membrane-associated protein 7; TBK1, Tank-binding kinase 1; WIPI2, WD repeat domain phosphoinositide-interacting protein 2.