Cell death and infection: A double-edged sword for host and pathogen survival

Ashida, Hiroshi; Mimuro, Hitomi; Ogawa, Michinaga; Kobayashi, Taira; Sanada, Takahito; Kim, Minsoo; Sasakawa, Chihiro

doi:10.1083/jcb.201108081

Cited by 307 publications

(258 citation statements)

References 102 publications

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“…Although it is recognized that pathogens can modulate programmed cell death pathways, including apoptosis, pyroptosis, and necroptosis (2,5), previous studies examining N. gonorrhoeae have focused primarily on the apoptosis pathway (17)(18)(19)21). In this study, we demonstrated that N. gonorrhoeae does not induce apoptosis in End/E6E7 cells as measured by changes in phosphatidylserine and caspase-3, confirming previous studies (21).…”

Section: Discussionsupporting

confidence: 78%

“…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)(4)(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).…”

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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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Section: Discussionsupporting

confidence: 78%

mentioning

confidence: 99%

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

2015

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“…The elimination of infected cells via apoptosis is an evolutionarily conserved defense mechanism (30). So it is not surprising that % fragmented nuclei…”

Section: Discussionmentioning

confidence: 99%

Antiapoptotic Activity of Coxiella burnetii Effector Protein AnkG Is Controlled by p32-Dependent Trafficking

et al. 2014

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c Intracellular bacterial pathogens frequently inhibit host cell apoptosis to ensure survival of their host, thereby allowing bacterial propagation. The obligate intracellular pathogen Coxiella burnetii displays antiapoptotic activity which depends on a functional type IV secretion system (T4SS). Accordingly, antiapoptotic T4SS effector proteins, like AnkG, have been identified. AnkG inhibits pathogen-induced apoptosis, possibly by binding to the host cell mitochondrial protein p32 (gC1qR). However, the molecular mechanism of AnkG activity remains unknown. Here, we demonstrate that ectopically expressed AnkG associates with mitochondria and traffics into the nucleus after apoptosis induction, although AnkG lacks a predicted nuclear localization signal. We identified the p32 interaction region in AnkG and constructed an AnkG mutant (AnkG R22/23S ) unable to bind to p32. By using this mutant, we found that intracellular localization and trafficking of AnkG into the nucleus are dependent on binding to p32. Furthermore, we demonstrated that nuclear localization of AnkG but not binding to p32 is required for apoptosis inhibition. Thus, the antiapoptotic activity of AnkG is controlled by p32-mediated intracellular trafficking, which, in turn, seems to be regulated by host cell processes that sense stress.

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“…In response to intracellular bacterial infection, at least two major types of cell death might occur: pyroptosis and apoptosis (8,9). Through detection of bacterial components such as flagellin and the conserved inner rod protein of T3SS, infected macrophages are induced to assemble inflammasome complexes in which caspase-1 is activated.…”

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confidence: 99%

Edwardsiella tarda-Induced Cytotoxicity Depends on Its Type III Secretion System and Flagellin

et al. 2014

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bMany Gram-negative bacteria utilize a type III secretion system (T3SS) to translocate virulence proteins into host cells to cause diseases. In responding to infection, macrophages detect some of the translocated proteins to activate caspase-1-mediated cell death, called pyroptosis, and secretion of proinflammatory cytokines to control the infection. Edwardsiella tarda is a Gram-negative enteric pathogen that causes hemorrhagic septicemia in fish and both gastrointestinal and extraintestinal infections in humans. In this study, we report that the T3SS of E. tarda facilitates its survival and replication in murine bone marrow-derived macrophages, and E. tarda infection triggers pyroptosis of infected macrophages from mice and fish and increased secretion of the cytokine interleukin 1␤ in a T3SS-dependent manner. Deletion of the flagellin gene fliC of E. tarda results in decreased cytotoxicity for infected macrophages and does not attenuate its virulence in a fish model of infection, whereas upregulated expression of FliC in the fliC mutant strain reduces its virulence. We propose that the host controls E. tarda infection partially by detecting FliC translocated by the T3SS, whereas the bacteria downregulate the expression of FliC to evade innate immunity.

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Cell death and infection: A double-edged sword for host and pathogen survival

Cited by 307 publications

References 102 publications

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

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

Antiapoptotic Activity of Coxiella burnetii Effector Protein AnkG Is Controlled by p32-Dependent Trafficking

Edwardsiella tarda-Induced Cytotoxicity Depends on Its Type III Secretion System and Flagellin

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