<i>Salmonella</i>exploits host Rho GTPase signalling pathways through the phosphatase activity of SopB

Truong, Dorothy; Boddy, Kirsten C.; Canadien, Veronica; Brabant, Danielle; Fairn, Gregory D.; D’Costa, Vanessa M.; Coyaud, Étienne; Raught, Brian; Park, Wei Sun; Heo, Won Do; Grinstein, Sergio; Brumell, John H.

doi:10.1111/cmi.12938

Cited by 28 publications

(31 citation statements)

References 80 publications

(137 reference statements)

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“…The data reveal that TTSS-1-dependent S .Tm invasion of human monocytes and macrophages rely on a highly similar effector program as the one used for ruffle-mediated entry in epithelial cell lines. Consequently, actin modulation through the combined action of the lipid phosphatase SopB (17–19) and the Rho-GEFs SopE (20) and SopE2 (21) constitutes a generic program for TTSS-1-dependent entry across epithelial and blood-derived cell types. It remains to be explored whether this will also hold true for other host cell types and for primary cells/tissues in vivo .…”

Section: Discussionmentioning

confidence: 99%

“…SipA works in concert with the TTSS-1 translocon component SipC to drive actin nucleation (14) and further stabilizes and protects actin filaments from the depolymerizing activities of, e.g., ADF/cofilin and Gelsolin (15, 16). SopB is a lipid phosphatase that alters the phosphatidylinositol-phosphate composition of the plasma membrane inner leaflet, thereby indirectly recruiting cellular Rho GTPases (17–19). SopE and SopE2 function as guanine nucleotide exchange factors (GEFs) that directly activate Rho GTPases, including Cdc42 and Rac1 (20, 21).…”

Section: Introductionmentioning

confidence: 99%

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Barcoded Consortium Infections Resolve Cell Type-Dependent Salmonella enterica Serovar Typhimurium Entry Mechanisms

Martino

Hardt

et al. 2019

mBio

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Bacterial host cell invasion mechanisms depend on the bacterium’s virulence factors and the properties of the target cell. The enteropathogen Salmonella enterica serovar Typhimurium (S.Tm) invades epithelial cell types in the gut mucosa and a variety of immune cell types at later infection stages. The molecular mechanism(s) of host cell entry has, however, been studied predominantly in epithelial cell lines. S.Tm uses a type three secretion system (TTSS-1) to translocate effectors into the host cell cytosol, thereby sparking actin ruffle-dependent entry. The ruffles also fuel cooperative invasion by bystander bacteria. In addition, several TTSS-1-independent entry mechanisms exist, involving alternative S.Tm virulence factors, or the passive uptake of bacteria by phagocytosis. However, it remains ill-defined how S.Tm invasion mechanisms vary between host cells. Here, we developed an internally controlled and scalable method to map S.Tm invasion mechanisms across host cell types and conditions. The method relies on host cell infections with consortia of chromosomally tagged wild-type and mutant S.Tm strains, where the abundance of each strain can be quantified by qPCR or amplicon sequencing. Using this methodology, we quantified cooccurring TTSS-1-dependent, cooperative, and TTSS-1-independent invasion events in epithelial, monocyte, and macrophage cells. We found S.Tm invasion of epithelial cells and monocytes to proceed by a similar MOI-dependent mix of TTSS-1-dependent and cooperative mechanisms. TTSS-1-independent entry was more frequent in macrophages. Still, TTSS-1-dependent invasion dominated during the first minutes of interaction also with this cell type. Finally, the combined action of the SopB/SopE/SopE2 effectors was sufficient to explain TTSS-1-dependent invasion across both epithelial and phagocytic cells. IMPORTANCE Salmonella enterica serovar Typhimurium (S.Tm) is a widespread and broad-host-spectrum enteropathogen with the capacity to invade diverse cell types. Still, the molecular basis for the host cell invasion process has largely been inferred from studies of a few selected cell lines. Our work resolves the mechanisms that Salmonellae employ to invade prototypical host cell types, i.e., human epithelial, monocyte, and macrophage cells, at a previously unattainable level of temporal and quantitative precision. This highlights efficient bacterium-driven entry into innate immune cells and uncovers a type III secretion system effector module that dominates active bacterial invasion of not only epithelial cells but also monocytes and macrophages. The results are derived from a generalizable method, where we combine barcoding of the bacterial chromosome with mixed consortium infections of cultured host cells. The application of this methodology across bacterial species and infection models will provide a scalable means to address host-pathogen interactions in diverse contexts.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Barcoded Consortium Infections Resolve Cell Type-Dependent Salmonella enterica Serovar Typhimurium Entry Mechanisms

Martino

Hardt

et al. 2019

mBio

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“…SopB-TRAF6 interactions prevent the recruitment of TRAF6 to the mitochondria, inhibiting accumulation of ROS in the organelle, thus preventing intrinsic apoptosis (56). SopB phosphatase activity in epithelial cells also mediates the recruitment of Rho and Ras family GTPases to the site of infection, promoting pro-survival Akt signaling and inhibiting apoptotic responses downstream (57–59). Another SPI-1 translocated effector that alters apoptotic pathways is AvrA, which displays deubiquitinase and acetyl-transferase activity.…”

Section: Apoptotic Cell Death Pathways During Salmonella Infectionmentioning

confidence: 99%

Host Cell Death Responses to Non-typhoidal Salmonella Infection

Wemyss

Pearson

2019

Front. Immunol.

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Salmonella enterica subsp. enterica serovar Typhimurium ( S . Typhimurium) is a Gram-negative bacterium with a broad host range that causes non-typhoidal salmonellosis in humans. S . Typhimurium infects epithelial cells and macrophages in the small intestine where it replicates in a specialized intracellular niche called the Salmonella -containing vacuole (SCV) and promotes inflammation of the mucosa to induce typically self-limiting gastroenteritis. Virulence and spread of the bacterium is determined in part by the host individual's ability to limit the infection through innate immune responses at the gastrointestinal mucosa, including programmed cell death. S . Typhimurium however, has evolved a myriad of mechanisms to counteract or exploit host responses through the use of Type III Secretion Systems (T3SS), which allow the translocation of virulence (effector) proteins into the host cell for the benefit of optimal bacterial replication and dissemination. T3SS effectors have been found to interact with apoptotic, necroptotic, and pyroptotic cell death cascades, interfering with both efficient clearance of the bacteria and the recruitment of neutrophils or dendritic cells to the area of infection. The interplay of host inflammation, programmed cell death responses, and bacterial defenses in the context of non-typhoidal Salmonella (NTS) infection is a continuing area of interest within the field, and as such has been reviewed here.

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“…SopB carries a lipid phosphatase activity that alters the phosphatidylinositol-phosphate (PIP) composition of the plasma membrane inner leaflet [13]. This indirectly recruits multiple host factors, including Rho-GTPases and their activating Guanine nucleotide Exchange Factors (GEFs) to sites of bacterial docking [14,15]. SopE and SopE2 mimic cellular GEFs to directly activate actin-regulatory GTPases, such as Rac1 and Cdc42 [8,9].…”

Section: Introductionmentioning

confidence: 99%

Salmonella Typhimurium discreet-invasion of the murine gut absorptive epithelium

et al. 2020

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Salmonella enterica serovar Typhimurium (S.Tm) infections of cultured cell lines have given rise to the ruffle model for epithelial cell invasion. According to this model, the Type-Three-Secretion-System-1 (TTSS-1) effectors SopB, SopE and SopE2 drive an explosive actin nucleation cascade, resulting in large lamellipodia-and filopodia-containing ruffles and cooperative S.Tm uptake. However, cell line experiments poorly recapitulate many of the cell and tissue features encountered in the host's gut mucosa. Here, we employed bacterial genetics and multiple imaging modalities to compare S.Tm invasion of cultured epithelial cell lines and the gut absorptive epithelium in vivo in mice. In contrast to the prevailing rufflemodel, we find that absorptive epithelial cell entry in the mouse gut occurs through "discreetinvasion". This distinct entry mode requires the conserved TTSS-1 effector SipA, involves modest elongation of local microvilli in the absence of expansive ruffles, and does not favor cooperative invasion. Discreet-invasion preferentially targets apicolateral hot spots at cellcell junctions and shows strong dependence on local cell neighborhood. This proof-of-principle evidence challenges the current model for how S.Tm can enter gut absorptive epithelial cells in their intact in vivo context.

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Salmonellaexploits host Rho GTPase signalling pathways through the phosphatase activity of SopB

Cited by 28 publications

References 80 publications

Barcoded Consortium Infections Resolve Cell Type-Dependent Salmonella enterica Serovar Typhimurium Entry Mechanisms

Barcoded Consortium Infections Resolve Cell Type-Dependent Salmonella enterica Serovar Typhimurium Entry Mechanisms

Host Cell Death Responses to Non-typhoidal Salmonella Infection

Salmonella Typhimurium discreet-invasion of the murine gut absorptive epithelium

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