Microarray analysis of Shigella flexneri-infected epithelial cells identifies host factors important for apoptosis inhibition

Faherty, Christina S.; Merrell, D. Scott; Semino–Mora, Cristina; Dubois, A.; Ramaswamy, Aishwarya V.; Maurelli, Anthony T.

doi:10.1186/1471-2164-11-272

Cited by 17 publications

(12 citation statements)

References 89 publications

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“…For example, Ehrlichia, Neisseria, Salmonella, and Chlamydia inhibit cytochrome c release from mitochondria (62)(63)(64)(65), Bartonella, Rickettsia, and enteropathogenic E. coli disrupt signaling pathways leading to the induction of apoptosis (66)(67)(68), and Shigella and Legionella modulate the activity of proapoptotic caspases (69,70). Although a role for multidrug efflux in modulation of host inflammatory responses has been described in Listeria monocytogenes (71), none of the antiapoptotic activities characterized to date for intracellular pathogens has been attributed directly to TolC or the type I secretion system.…”

Section: Discussionmentioning

confidence: 99%

TolC-Dependent Modulation of Host Cell Death by the Francisella tularensis Live Vaccine Strain

et al. 2014

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Francisella tularensis is a facultative intracellular, Gram-negative pathogen and the causative agent of tularemia. We previously identified TolC as a virulence factor of the F. tularensis live vaccine strain (LVS) and demonstrated that a ⌬tolC mutant exhibits increased cytotoxicity toward host cells and elicits increased proinflammatory responses compared to those of the wild-type (WT) strain. TolC is the outer membrane channel component used by the type I secretion pathway to export toxins and other bacterial virulence factors. Here, we show that the LVS delays activation of the intrinsic apoptotic pathway in a TolC-dependent manner, both during infection of primary macrophages and during organ colonization in mice. The TolC-dependent delay in host cell death is required for F. tularensis to preserve its intracellular replicative niche. We demonstrate that TolC-mediated inhibition of apoptosis is an active process and not due to defects in the structural integrity of the ⌬tolC mutant. These findings support a model wherein the immunomodulatory capacity of F. tularensis relies, at least in part, on TolC-secreted effectors. Finally, mice vaccinated with the ⌬tolC LVS are protected from lethal challenge and clear challenge doses faster than WT-vaccinated mice, demonstrating that the altered host responses to primary infection with the ⌬tolC mutant led to altered adaptive immune responses. Taken together, our data demonstrate that TolC is required for temporal modulation of host cell death during infection by F. tularensis and highlight how shifts in the magnitude and timing of host innate immune responses may lead to dramatic changes in the outcome of infection.

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Section: Discussionmentioning

confidence: 99%

TolC-Dependent Modulation of Host Cell Death by the Francisella tularensis Live Vaccine Strain

et al. 2014

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“…The strategy of stabilizing anti-apoptotic proteins is a common approach for inhibiting caspase-3 utilized by bacterial pathogens. S. flexneri uses a combination of these approaches, including up-regulating the IAP family (Faherty et al , 2010). In addition, S. flexneri inhibits caspase-3 through a membrane expression of invasion plasmid antigen E (MxiE)-dependent mechanism that may involve direct binding of caspase-3 or caspase-9 (Clark and Maurelli, 2007).…”

Section: Inhibition Of Caspase-3 By Bacterial Pathogensmentioning

confidence: 99%

“…Indeed, such subversion occurs at nearly all points of the apoptotic cascade with different bacterial pathogens having evolved distinct modes to induce or inhibit specific apoptotic pathways in an attempt to manipulate the lifespan of infected cells and/or influence their behaviour in a manner that supports infection. Therefore, the critical role caspases play in determining cellular fate makes these serine proteases a high-risk target for bacterial pathogens, but when successfully manipulated, Protects intracellular replication niche Clark and Maurelli, 2007;Faherty and Maurelli, 2009;Faherty et al, 2010 Activation of caspase-3 by individual effectors is indicated as well as whether this activation is potentially direct or through upstream initiator or other caspases. ND indicates that the mechanism of activation of caspase-3 or the involvement of other caspases was not defined in the study.…”

Section: Apoptosis and Bacterial Infectionmentioning

confidence: 99%

Bacterial secreted effectors and caspase‐3 interactions

Wall

McCormick

2014

Cell Microbiol

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Apoptosis is a critical process that intrinsically links organism survival to its ability to induce controlled death. Thus, functional apoptosis allows organisms to remove perceived threats to their survival by targeting those cells that it determines pose a direct risk. Central to this process are apoptotic caspases, enzymes that form a signalling cascade, converting danger signals via initiator caspases into activation of the executioner caspase, caspase-3. This enzyme begins disassembly of the cell by activating DNA degrading enzymes and degrading the cellular architecture. Interaction of pathogenic bacteria with caspases, and in particular, caspase-3, can therefore impact both host cell and bacterial survival. With roles outside cell death such as cell differentiation, control of signalling pathways and immunomodulation also being described for caspase-3, bacterial interactions with caspase-3 may be of far more significance in infection than previously recognized. In this review, we highlight the ways in which bacterial pathogens have evolved to subvert caspase-3 both through effector proteins that directly interact with the enzyme or by modulating pathways that influence its activation and activity.

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“…flexneri infection of epithelial cells has been well investigated by reductionist approaches that led to important findings regarding specific molecular aspects of infection, and general concepts of infection biology and immunology (26,27). In addition, DNA microarrays were instrumental in the systematic identification of genes regulated during infection and the characterization of host cell responses (28,29). However, these approaches were not well-suited to obtain a systems-level overview of early host signaling during infection.…”

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confidence: 99%

Systems-Level Overview of Host Protein Phosphorylation During Shigella flexneri Infection Revealed by Phosphoproteomics

Schmutz

Ahrné

Kasper

et al. 2013

Molecular & Cellular Proteomics

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The enteroinvasive bacterium Shigella flexneri invades the intestinal epithelium of humans. During infection, several injected effector proteins promote bacterial internalization, and interfere with multiple host cell responses. To obtain a systems-level overview of host signaling during infection, we analyzed the global dynamics of protein phosphorylation by liquid chromatography-tandem MS and identified several hundred of proteins undergoing a phosphorylation change during the first hours of infection. Functional bioinformatic analysis revealed that they were mostly related to the cytoskeleton, transcription, signal transduction, and cell cycle. Fuzzy c-means clustering identified six temporal profiles of phosphorylation and a functional module composed of ATM-phosphorylated proteins related to genotoxic stress. Pathway enrichment analysis defined mTOR as the most overrepresented pathway. We showed that mTOR complex 1 and 2 were required for S6 kinase and AKT activation, respectively. Comparison with a published phosphoproteome of Salmonella typhimuriuminfected cells revealed a large subset of coregulated phosphoproteins. Finally, we showed that S. flexneri effector OspF affected the phosphorylation of several hundred proteins, thereby demonstrating the wide-reaching impact of a single bacterial effector on the host signaling network. Molecular & Cellular

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Microarray analysis of Shigella flexneri-infected epithelial cells identifies host factors important for apoptosis inhibition

Cited by 17 publications

References 89 publications

TolC-Dependent Modulation of Host Cell Death by the Francisella tularensis Live Vaccine Strain

TolC-Dependent Modulation of Host Cell Death by the Francisella tularensis Live Vaccine Strain

Bacterial secreted effectors and caspase‐3 interactions

Systems-Level Overview of Host Protein Phosphorylation During Shigella flexneri Infection Revealed by Phosphoproteomics

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