title: Neisseria gonorrhoeae Modulates Cell Death in Human Endocervical Epithelial Cells through Export of Exosome-Associated cIAP2.
abstract: 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-1β (IL-1β) 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.
authors.affiliation: Department of Medicine, Section of Infectious Diseases, Boston University School of Medicine, Boston, Massachusetts, USA.
authors.forename: Kathleen
authors.identifier: http://orcid.org/0000-0002-5483-0515
authors.initials: K
authors.lastname: Nudel
authors.affiliation: Department of Medicine, Section of Infectious Diseases, Boston University School of Medicine, Boston, Massachusetts, USA.
authors.forename: Paola
authors.initials: P
authors.lastname: Massari
authors.affiliation: Department of Medicine, Section of Infectious Diseases, Boston University School of Medicine, Boston, Massachusetts, USA Department of Microbiology, Boston University School of Medicine, Boston, Massachusetts, USA caroline.genco@tufts.edu.
authors.forename: Caroline A
authors.initials: CA
authors.lastname: Genco
mesh_terms: D017209:Apoptosis / Q000502:physiology*; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; D015153:Blotting, Western; D002460:Cell Line; D002584:Cervix Uteri / Q000382:microbiology; D004797:Enzyme-Linked Immunosorbent Assay; D004847:Epithelial Cells / Q000378:metabolism* / Q000382:microbiology; D055354:Exosomes / Q000378:metabolism*; D005260:Female; D005434:Flow Cytometry; D006069:Gonorrhea / Q000378:metabolism*; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism*; D009344:Neisseria gonorrhoeae / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*
chemical_list: D051034:Inhibitor of Apoptosis Proteins; C494832:BIRC3 protein, human; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; D044767:Ubiquitin-Protein Ligases