<i>Neisseria gonorrhoeae</i>
            Infection Protects Human Endocervical Epithelial Cells from Apoptosis via Expression of Host Antiapoptotic Proteins

Follows, S. A.; Murlidharan, J.; Massi, Paola; Wetzler, Lee M.; Genco, Caroline Attardo

doi:10.1128/iai.01366-08

Cited by 28 publications

(42 citation statements)

References 69 publications

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“…The initial attachment of the bacteria to the apical surface of epithelial tissues is mediated by type IV pili (Källström et al, 1997;Merz et al, 1999;Merz et al, 1996;Swanson, 1973). The adherence mediates host cell-signaling events and elicits a multitude of cellular responses, including cortical plaque formation (Merz et al, 1999), the release of intracellular calcium (Källström et al, 2000;Källström et al, 1998), and the induction of anti-apoptotic factors (Binnicker et al, 2003;Follows et al, 2009). During N. gonorrhoeae infection, several signaling pathways are induced by virulence factors such as porins, lipooligosaccharides, iron receptors, outer membrane vesicles, and pilus biogenesis-associated proteins (for reviews, see Popp et al, 2001;Koomey, 2001).…”

Section: Introductionmentioning

confidence: 99%

Neisseria gonorrhoeae infection causes DNA damage and affects the expression of p21, p27 and p53 in non-tumor epithelial cells

Vielfort

Söderholm

Weyler

et al. 2013

Journal of Cell Science

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SummaryThe constant shedding and renewal of epithelial cells maintain the protection of epithelial barriers. Interference with the processes of host cell-cycle regulation and barrier integrity permits the bacterial pathogen Neisseria gonorrhoeae to effectively colonize and invade epithelial cells. Here, we show that a gonococcal infection causes DNA damage in human non-tumor vaginal VK2/E6E7 cells with an increase of 700 DNA strand breaks per cell per hour as detected by an alkaline DNA unwinding assay. Infected cells exhibited elevated levels of DNA double-strand breaks, as indicated by a more than 50% increase in cells expressing DNA damage-response protein 53BP1-positive foci that co-localized with phosphorylated histone H2AX (cH2AX). Furthermore, infected cells abolished their expression of the tumor protein p53 and induced an increase in the expression of cyclin-dependent kinase inhibitors p21 and p27 to 2.6-fold and 4.2-fold of controls, respectively. As shown by live-cell microscopy, flow cytometry assays, and BrdU incorporation assays, gonococcal infection slowed the host cell-cycle progression mainly by impairing progression through the G2 phase. Our findings show new cellular players that are involved in the control of the human cell cycle during gonococcal infection and the potential of bacteria to cause cellular abnormalities.

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Section: Introductionmentioning

confidence: 99%

Neisseria gonorrhoeae infection causes DNA damage and affects the expression of p21, p27 and p53 in non-tumor epithelial cells

Vielfort

Söderholm

Weyler

et al. 2013

Journal of Cell Science

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“…Our group and others have reported that N. gonorrhoeae manipulates cell death pathways, either inducing or preventing cell death, in different cell types (16)(17)(18)(19)(20)(21). We demonstrated that N. gonorrhoeae protects human endocervical epithelial cells from apoptosis, likely as a mechanism to maintain an intracellular niche and evade immune clearance (21). We also reported that N. gonorrhoeae stimulation of human endocervical epithelial cells resulted in a significantly increased expression of the inhibitor of apoptosis-2 (cIAP2) (21).…”

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confidence: 80%

“…We demonstrated that N. gonorrhoeae protects human endocervical epithelial cells from apoptosis, likely as a mechanism to maintain an intracellular niche and evade immune clearance (21). We also reported that N. gonorrhoeae stimulation of human endocervical epithelial cells resulted in a significantly increased expression of the inhibitor of apoptosis-2 (cIAP2) (21). cIAP2, cIAP1, survivin, and XIAP are members of the inhibitor of apoptosis family, which contain the signature baculoviral inhibitor of apoptosis repeat (BIR).…”

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confidence: 99%

“…Epithelial cells shape the tissue immune microenvironment by producing cytokines and chemokines (10,11), releasing cellular factors such as damage-associated molecular patterns (DAMPs) (12,13) that can further activate immune cells and via production of antimicrobial peptides that control infecting microorganisms (14,15). Our group and others have reported that N. gonorrhoeae manipulates cell death pathways, either inducing or preventing cell death, in different cell types (16)(17)(18)(19)(20)(21). We demonstrated that N. gonorrhoeae protects human endocervical epithelial cells from apoptosis, likely as a mechanism to maintain an intracellular niche and evade immune clearance (21).…”

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confidence: 99%

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Neisseria gonorrhoeae Modulates Cell Death in Human Endocervical Epithelial Cells through Export of Exosome-Associated cIAP2

2015

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Several bacterial pathogens persist and survive in the host by modulating host cell death pathways. We previously demonstrated that Neisseria gonorrhoeae, a Gram-negative pathogen responsible for the sexually transmitted infection gonorrhea, protects against exogenous induction of apoptosis in human cervical epithelial cells. However, induction of cell death by N. gonorrhoeae has also been reported in other cell types. The mechanisms by which N. gonorrhoeae modulates cell death are not clear, although a role for the inhibitor of apoptosis-2 (cIAP2) has been proposed. In this study, we confirmed that N. gonorrhoeae induces production of cIAP2 in human cervical epithelial cells. High levels of intracellular cIAP2 were detected early after N. gonorrhoeae stimulation, which was followed by a marked decrease at 24 h. At this time point, we observed increased levels of extracellular cIAP2 associated with exosomes and an overall increase in production of exosomes. Inhibition of cIAP2 in N. gonorrhoeae-stimulated epithelial cells resulted in increased cell death and interleukin-1␤ (IL-1␤) production. Collectively these results indicate that N. gonorrhoeae stimulation of human endocervical epithelial cells induces the release of cIAP2, an essential regulator of cell death and immune signaling. The induction of programmed cell death is a common host response to bacterial pathogens and typically results in clearance by phagocytic immune cells (1). Release of inflammatory mediators by dying cells further influences immune responses, tightly coupling cell death and inflammation during bacterial infection (2). While repression of cell death pathways favors host cell survival, induction of cell death can be beneficial for pathogens. Accordingly, pathogens often manipulate such cell death pathways to favor their own replication and persistence (3-5). Apoptosis, pyroptosis, and necroptosis are programmed cell death pathways with distinct inflammatory outcomes; apoptosis is noninflammatory, while pyroptosis and necroptosis are highly inflammatory (6). Each of these pathways can be initiated or repressed by different pathogens and in different cell types.Neisseria gonorrhoeae is a Gram-negative diplococcus responsible for the sexually transmitted infection gonorrhea. Infection of the female genital tract by this organism is localized at the cervix, in both endocervical and ectocervical epithelial cells (7). Epithelial cells are the first responders and orchestrators of the early innate immune response during mucosal infection (8, 9). Epithelial cells shape the tissue immune microenvironment by producing cytokines and chemokines (10, 11), releasing cellular factors such as damage-associated molecular patterns (DAMPs) (12, 13) that can further activate immune cells and via production of antimicrobial peptides that control infecting microorganisms (14, 15). Our group and others have reported that N. gonorrhoeae manipulates cell death pathways, either inducing or preventing cell death, in different cell types (16)(17)(18)(19)(20)(21)....

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“…In other cell types, both protection from (47,48) and promotion of (49) cell death have been observed upon infection with N. gonorrhoeae. Although the majority of studies examining this effect have focused on epithelial cells, it is becoming clear that infection with N. gonorrhoeae, more often than not, inhibits apoptosis (50).…”

Section: Discussionmentioning

confidence: 99%

Vigorous Response of Human Innate Functioning IgM Memory B Cells upon Infection by Neisseria gonorrhoeae

Ostrowski

Gray-Owen

2012

The Journal of Immunology

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Neisseria gonorrhoeae, the cause of the sexually transmitted infection gonorrhea, elicits low levels of specific Ig that decline rapidly after the bacteria are cleared. Reinfection with the same serovar can occur, and prior gonococcal infection does not alter the Ig response upon subsequent exposure, suggesting that protective immunity is not induced. The mucosal Ig response apparent during gonorrhea does not correlate with that observed systemically, leading to a suggestion that it is locally generated. In considering whether N. gonorrhoeae directly influences B cells, we observed that gonococcal infection prolonged viability of primary human B cells in vitro and elicited robust activation and vigorous proliferative responses in the absence of T cells. Furthermore, we observed the specific expansion of IgD+CD27+ B cells in response to gonococcal infection. These cells are innate in function, conferring protection against diverse microbes by producing low-affinity, broadly reactive IgM without inducing classical immunologic memory. Although gonococcal infection of B cells produced small amounts of gonococcal-specific IgM, IgM specific for irrelevant Ags were also produced, suggesting a broad, polyspecific Ig response. The gonococci were effectively bound and engulfed by B cells. TLR9-inhibitory CpGs blocked B cell responses, indicating that intracellular bacterial degradation allows for innate immune detection within the phagolysosome. To our knowledge, this is the first report of a bacterial pathogen having specific affinity for the human IgM memory B cells, driving their potent activation and polyclonal Ig response. This unfocused T-independent response explains the localized Ig response that occurs, despite an absence of immunologic memory elicited during gonorrhea.

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Neisseria gonorrhoeae Infection Protects Human Endocervical Epithelial Cells from Apoptosis via Expression of Host Antiapoptotic Proteins

Cited by 28 publications

References 69 publications

Neisseria gonorrhoeae infection causes DNA damage and affects the expression of p21, p27 and p53 in non-tumor epithelial cells

Neisseria gonorrhoeae infection causes DNA damage and affects the expression of p21, p27 and p53 in non-tumor epithelial cells

Neisseria gonorrhoeae Modulates Cell Death in Human Endocervical Epithelial Cells through Export of Exosome-Associated cIAP2

Vigorous Response of Human Innate Functioning IgM Memory B Cells upon Infection by Neisseria gonorrhoeae

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