Neisseria gonorrhoeae-Mediated Inhibition of Apoptotic Signalling in Polymorphonuclear Leukocytes

Chen, Adrienne; Seifert, H. Steven

doi:10.1128/iai.01267-10

Cited by 45 publications

(67 citation statements)

References 75 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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“…Cells were incubated for 10 min at 37°C, followed by stimulation with P. aeruginosa strain PAK at a multiplicity of infection (MOI) of 30. Phorbol myristate acetate (PMA) (100 ng/ml) was used as a positive control to stimulate ROS production by differentiated HL-60 cells (19). ROS production was monitored every 2 to 5 min for 2 h with a luminometer (Varioskan Flash, Thermo Scientific).…”

Section: Methodsmentioning

confidence: 99%

“…The media were supplemented with 10% (vol/vol) heat-inactivated fetal bovine serum (hiFBS), penicillin G (100 U/ml), and streptomycin (100 g/ml) at 37°C in 5% (vol/vol) CO 2 . The HL-60 cell differentiation was performed as previously described (19). Briefly, HL-60 cells were diluted to no more than 4.5 ϫ 10 5 cells per ml, followed by treatment with 1.3% dimethyl sulfoxide (Sigma) for a period of 6 to 9 days.…”

Section: Methodsmentioning

confidence: 99%

PrtR Homeostasis Contributes to Pseudomonas aeruginosa Pathogenesis and Resistance against Ciprofloxacin

et al. 2014

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bPseudomonas aeruginosa is an opportunistic pathogen that causes acute and chronic infections in humans. Pyocins are bacteriocins produced by P. aeruginosa that are usually released through lysis of the producer strains. Expression of pyocin genes is negatively regulated by PrtR, which gets cleaved under SOS response, leading to upregulation of pyocin synthetic genes. Previously, we demonstrated that PrtR is required for the expression of type III secretion system (T3SS), which is an important virulence component of P. aeruginosa. In this study, we demonstrate that mutation in prtR results in reduced bacterial colonization in a mouse acute pneumonia model. Examination of bacterial and host cells in the bronchoalveolar lavage fluids from infected mice revealed that expression of PrtR is induced by reactive oxygen species (ROS) released by neutrophils. We further demonstrate that treatment with hydrogen peroxide or ciprofloxacin, known to induce the SOS response and pyocin production, resulted in an elevated PrtR mRNA level. Overexpression of PrtR by a tac promoter repressed the endogenous prtR promoter activity, and electrophoretic mobility shift assay revealed that PrtR binds to its own promoter, suggesting an autorepressive mechanism of regulation. A high level of PrtR expressed from a plasmid resulted in increased T3SS gene expression during infection and higher resistance against ciprofloxacin. Overall, our results suggest that the autorepression of PrtR contributes to the maintenance of a relatively stable level of PrtR, which is permissive to T3SS gene expression in the presence of ROS while increasing bacterial tolerance to stresses, such as ciprofloxacin, by limiting pyocin production.

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“…Bacteria expressing Opa proteins that engage neutrophil CEACAMs, particularly the granulocyte-specific CEACAM3, induce a potent oxidative burst in neutrophils ex vivo (23)(24)(25)(26)(27). In contrast, Opa-negative (Opa Ϫ ) Gc not only fails to induce ROS production in neutrophils, it also suppresses the neutrophil oxidative burst in response to other stimuli (28)(29)(30)(31)(32). Gc strains typically possess up to 11 Opa-encoding genes per genome, each of which undergoes phase variation between expressed and unexpressed states (22).…”

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confidence: 99%

Assembly of NADPH Oxidase in Human Neutrophils Is Modulated by the Opacity-Associated Protein Expression State of Neisseria gonorrhoeae

2014

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Neisseria gonorrhoeae (the gonococcus, Gc) triggers a potent inflammatory response and recruitment of neutrophils to the site of infection. Gc survives exposure to neutrophils despite these cells' antimicrobial products, such as reactive oxygen species (ROS). ROS production in neutrophils is initiated by NADPH oxidase, which converts oxygen into superoxide. The subunits of NADPH oxidase are spatially separated between granules (gp91 phox /p22 phox ) and the cytoplasm (p47 phox , p67 phox , and p40 phox ). Activation of neutrophils promotes the coassembly of NADPH oxidase subunits at phagosome and/or plasma membranes. While Gc-expressing opacity-associated (Opa) proteins can induce neutrophils to produce ROS, Opa-negative (Opa ؊ ) Gc does not stimulate neutrophil ROS production. Using constitutively Opa ؊ and OpaD-positive (OpaD ؉ ) Gc bacteria in strain FA1090, we now show that the difference in ROS production levels in primary human neutrophils between these backgrounds can be attributed to differential assembly of NADPH oxidase. Neutrophils infected with Opa ؊ Gc showed limited translocation of NADPH oxidase cytoplasmic subunits to cellular membranes, including the bacterial phagosome. In contrast, these subunits rapidly translocated to neutrophil membranes following infection with OpaD ؉ Gc. gp91 phox and p22 phox were recruited to Gc phagosomes regardless of bacterial Opa expression. These results suggest that Opa ؊ Gc interferes with the recruitment of neutrophil NADPH oxidase cytoplasmic subunits to membranes, in particular, the p47 phox "organizing" subunit, to prevent assembly of the holoenzyme, resulting in an absence of the oxidative burst.

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Neisseria gonorrhoeae-Mediated Inhibition of Apoptotic Signalling in Polymorphonuclear Leukocytes

Cited by 45 publications

References 75 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

PrtR Homeostasis Contributes to Pseudomonas aeruginosa Pathogenesis and Resistance against Ciprofloxacin

Assembly of NADPH Oxidase in Human Neutrophils Is Modulated by the Opacity-Associated Protein Expression State of Neisseria gonorrhoeae

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