Dissemination of invasiveSalmonellavia bacterial-induced extrusion of mucosal epithelia

Abstract

Salmonella enterica is an intracellular bacterial pathogen that resides and proliferates within a membrane-bound vacuole in epithelial cells of the gut and gallbladder. Although essential to disease, how Salmonella escapes from its intracellular niche and spreads to secondary cells within the same host, or to a new host, is not known. Here, we demonstrate that a subpopulation of Salmonella hyperreplicating in the cytosol of epithelial cells serves as a reservoir for dissemination. These bacteria are transcriptionally distinct from intravacuolar Salmonella. They are induced for the invasion-associated type III secretion system and possess flagella; hence, they are primed for invasion. Epithelial cells laden with these cytosolic bacteria are extruded out of the monolayer, releasing invasion-primed and -competent Salmonella into the lumen. This extrusion mechanism is morphologically similar to the process of cell shedding required for turnover of the intestinal epithelium. In contrast to the homeostatic mechanism, however, bacterial-induced extrusion is accompanied by an inflammatory cell death characterized by caspase-1 activation and the apical release of IL-18, an important cytokine regulator of gut inflammation. Although epithelial extrusion is obviously beneficial to Salmonella for completion of its life cycle, it also provides a mechanistic explanation for the mucosal inflammation that is triggered during Salmonella infection of the gastrointestinal and biliary tracts.

RNA-Seq unveils new attributes of the heterogeneous Salmonella-host cell communication

“…18,19 Remarkably, in some instances both lifestyles are observed in the same infected cell. 18 The exact signals that drive S. Typhimurium to colonize the cytosol of the infected epithelial or to remain enclosed in a phagosomal compartment, remain unknown. Factors that may potentially predispose to a precise intracellular lifestyle in the pathogen include the phase of cell cycle in the host cell at the time it is invaded and/or an intrinsic variability in gene expression in the invading bacterium.…”

“…As the infection progresses in epithelial cells, subpopulations of cytosolic and intra-vacuolar intracellular bacteria evolve having distinct expression profiles for virulence determinants encoded by Salmonellapathogenicity islands 1 and 2 (SPI1 and SPI2). 18 These two intracellular lifestyles have been reported both in cultured epithelial cells and in vivo in enterocytes of infected mice. 18,19 Remarkably, in some instances both lifestyles are observed in the same infected cell.…”

“…18 These two intracellular lifestyles have been reported both in cultured epithelial cells and in vivo in enterocytes of infected mice. 18,19 Remarkably, in some instances both lifestyles are observed in the same infected cell. 18 The exact signals that drive S. Typhimurium to colonize the cytosol of the infected epithelial or to remain enclosed in a phagosomal compartment, remain unknown.…”

Maintenance of vacuole integrity by bacterial pathogens

“…It has been known for several years that a small percentage of Salmonella escape from the vacuole and reside in the cytosol of epithelial cells [38]. Recent work has shown that the bulk of Salmonella replication observed during growth in epithelial cells occurs in the cytosol; the significance of this during infection is unknown although it may play a role in bacterial dissemination [39,40]. Escape from the vacuole has also been observed for Mycobacterial species and L. pneumophila suggesting that an extra-vacuolar stage occurs in other bacterial infections [41][42][43].…”

Single-cell analysis: Understanding infected cell heterogeneity

“…In the mouse model of infection, bacteria reside in various cells of the immune system 10 or epithelial cells of the intestinal tract and gallbladder. 11 Low numbers of Salmonella have also been found in nonphagocytic stromal cells of the intestinal lamina propria that are probably fibroblasts. 12 In this cell type Salmonella actively restrain their proliferation.…”