Neisseria gonorrhoeae-derived heptose elicits an innate immune response and drives HIV-1 expression

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DOIResolve DOI: http://doi.org/10.1073/pnas.1303738110
AuthorSearch for: ; Search for: ; Search for: ; Search for: ; Search for: ; Search for: ; Search for: ; Search for: ; Search for: ; Search for: ; Search for:
TypeArticle
Journal titleProceedings of the National Academy of Sciences of the United States of America
ISSN0027-8424
Volume110
Issue25
Pages1023410239; # of pages: 6
Subjectheptose; heptose monophosphate; HldA protein; lipid A; toll like receptor 4; toll like receptor 5; unclassified drug; article; CD4+ T lymphocyte; Human immunodeficiency virus 1; innate immunity; mouse; mutagenesis; Neisseria gonorrhoeae; nonhuman; phenotype; priority journal; transposon; coinfection; inflammation; microbial-associated molecular pattern; pathogen-associated molecular pattern; sexually transmitted disease; Bacterial Proteins; CD4-Positive T-Lymphocytes; Coinfection; Female; Gonorrhea; Heptoses; HIV Infections; HIV Long Terminal Repeat; HIV-1; Humans; Jurkat Cells; Male; Neisseria gonorrhoeae; Toll-Like Receptor 5
AbstractClinical 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 genomewide 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 reporterbased 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. gonorrhoeaederived 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.
Publication date
LanguageEnglish
AffiliationNational Research Council Canada (NRC-CNRC)
Peer reviewedYes
NPARC number21270588
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Record identifier48de0760-5db0-49c4-827b-b4f74f2ff779
Record created2014-02-17
Record modified2016-05-09
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