title: Neisseria gonorrhoeae-derived heptose elicits an innate immune response and drives HIV-1 expression.
abstract: Clinical and epidemiological synergy exists between the globally important sexually transmitted infections, gonorrhea and HIV. Neisseria gonorrhoeae, which causes gonorrhea, is particularly adept at driving HIV-1 expression, but the molecular determinants of this relationship remain undefined. N. gonorrhoeae liberates a soluble factor that potently induces expression from the HIV-1 LTR in coinfected cluster of differentiation 4-positive (CD4(+)) T lymphocytes, but this factor is not a previously described innate effector. A genome-wide mutagenesis approach was undertaken to reveal which component(s) of N. gonorrhoeae induce HIV-1 expression in CD4(+) T lymphocytes. A mutation in the ADP-heptose biosynthesis gene, hldA, rendered the bacteria unable to induce HIV-1 expression. The hldA mutant has a truncated lipooligosaccharide structure, contains lipid A in its outer membrane, and remains bioactive in a TLR4 reporter-based assay but did not induce HIV-1 expression. Mass spectrometry analysis of extensively fractionated N. gonorrhoeae-derived supernatants revealed that the LTR-inducing fraction contained a compound having a mass consistent with heptose-monophosphate (HMP). Heptose is a carbohydrate common in microbes but is absent from the mammalian glycome. Although ADP-heptose biosynthesis is common among Gram-negative bacteria, and heptose is a core component of most lipopolysaccharides, N. gonorrhoeae is peculiar in that it effectively liberates HMP during growth. This N. gonorrhoeae-derived HMP activates CD4(+) T cells to invoke an NF-κB-dependent transcriptional response that drives HIV-1 expression and viral production. Our study thereby shows that heptose is a microbial-specific product that is sensed as an innate immune agonist and unveils the molecular link between N. gonorrhoeae and HIV-1.
authors.affiliation: Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada M5S 1A8.
authors.forename: Rebecca J
authors.initials: RJ
authors.lastname: Malott
authors.forename: Bernd O
authors.initials: BO
authors.lastname: Keller
authors.forename: Ryan G
authors.initials: RG
authors.lastname: Gaudet
authors.forename: Shannon E
authors.initials: SE
authors.lastname: McCaw
authors.forename: Christine C L
authors.initials: CC
authors.lastname: Lai
authors.forename: Wendy N
authors.initials: WN
authors.lastname: Dobson-Belaire
authors.forename: J Leigh
authors.initials: JL
authors.lastname: Hobbs
authors.forename: Frank
authors.initials: F
authors.lastname: St Michael
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Cox
authors.forename: Trevor F
authors.initials: TF
authors.lastname: Moraes
authors.forename: Scott D
authors.initials: SD
authors.lastname: Gray-Owen
mesh_terms: D001426:Bacterial Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000382:microbiology / Q000821:virology; D060085:Coinfection / Q000276:immunology*; D005260:Female; D006069:Gonorrhea / Q000276:immunology / Q000382:microbiology / Q000821:virology; D015658:HIV Infections / Q000276:immunology / Q000382:microbiology / Q000821:virology; D016325:HIV Long Terminal Repeat / Q000235:genetics; D015497:HIV-1 / Q000201:enzymology* / Q000276:immunology; D006539:Heptoses / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D019169:Jurkat Cells; D008297:Male; D009344:Neisseria gonorrhoeae / Q000201:enzymology* / Q000276:immunology; D051198:Toll-Like Receptor 5 / Q000276:immunology
chemical_list: D001426:Bacterial Proteins; D006539:Heptoses; C495346:TLR5 protein, human; D051198:Toll-Like Receptor 5
keywords: coinfection; inflammation; microbial-associated molecular pattern; pathogen-associated molecular pattern; sexually transmitted disease