title: Neisseria gonorrhoeae effectively blocks HIV-1 replication by eliciting a potent TLR9-dependent interferon-α response from plasmacytoid dendritic cells.
abstract: Clinical and epidemiological research provides evidence for a positive correlation between Neisseria gonorrhoeae infection and HIV transmission; however, mechanistic studies examining this relationship have yielded conflicting results. To explore this interaction, we exposed ex vivo cultured peripheral blood cells from acute HIV(+) individuals to N. gonorrhoeae. Unexpectedly, we observed a profound inhibition in HIV-1 replication in the ex vivo cultures, and this was recapitulated when peripheral blood mononuclear cells (PBMCs) from healthy donors were co-infected with HIV-1 and N. gonorrhoeae. Next, we established that gonococcal-infected PBMCs liberated a soluble factor that effectively blocked HIV-1 replication. Cytokine analyses and antibody blocking experiments revealed that the type I interferon, interferon-α (IFNα), was expressed upon exposure to N. gonorrhoeae and was responsible for the inhibition of HIV-1. Intracellular staining, TLR9-blocking and cell depletion-based studies demonstrated that the IFNα was elicited by plasmacytoid dendritic cells (pDCs) in a TLR9-dependent manner. The pDC response to N. gonorrhoeae was unexpected given pDCs more established role in innate defence against intracellular pathogens, suggesting this may be a bacterial immune evasion strategy. In the context of HIV, this overcomes the virus's otherwise effective avoidance of the interferon response and represents a previously unrecognized intersection between these two sexually transmitted pathogens.
authors.affiliation: Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Wendy N
authors.initials: WN
authors.lastname: Dobson-Belaire
authors.forename: Anuradha
authors.initials: A
authors.lastname: Rebbapragada
authors.forename: Rebecca J
authors.initials: RJ
authors.lastname: Malott
authors.forename: Feng Yun
authors.initials: FY
authors.lastname: Yue
authors.forename: Colin
authors.initials: C
authors.lastname: Kovacs
authors.forename: Rupert
authors.initials: R
authors.lastname: Kaul
authors.forename: Mario A
authors.initials: MA
authors.lastname: Ostrowski
authors.forename: Scott D
authors.initials: SD
authors.lastname: Gray-Owen
mesh_terms: D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology*; D015658:HIV Infections / Q000276:immunology / Q000382:microbiology / Q000821:virology; D015497:HIV-1 / Q000254:growth & development* / Q000276:immunology; D006801:Humans; D016898:Interferon-alpha / Q000096:biosynthesis / Q000276:immunology*; D007963:Leukocytes, Mononuclear / Q000382:microbiology* / Q000821:virology*; D009344:Neisseria gonorrhoeae / Q000254:growth & development* / Q000276:immunology; D051217:Toll-Like Receptor 9 / Q000276:immunology*; D014779:Virus Replication
chemical_list: D016898:Interferon-alpha; C495371:TLR9 protein, human; D051217:Toll-Like Receptor 9