Neisseria gonorrhoeae-derived heptose elicits an innate immune response and drives HIV-1 expression
| Autor: | Bernd O. Keller, Rebecca J. Malott, Shannon E. McCaw, Wendy N. Dobson-Belaire, Frank St. Michael, Trevor F. Moraes, Ryan G. Gaudet, Andrew D. Cox, J. Leigh Hobbs, Christine Chieh-Lin Lai, Scott D. Gray-Owen |
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| Rok vydání: | 2013 |
| Předmět: |
Sexually transmitted disease
CD4-Positive T-Lymphocytes Male transposon phenotype Human immunodeficiency virus 1 Heptose HIV Infections Biology medicine.disease_cause Microbiology toll like receptor 5 Lipid A Gonorrhea Jurkat Cells toll like receptor 4 Bacterial Proteins heptose monophosphate medicine Humans lipid A innate immunity mouse HIV Long Terminal Repeat chemistry.chemical_classification CD4+ T lymphocyte HldA protein Multidisciplinary Innate immune system heptose Effector Coinfection Pathogen-associated molecular pattern sexually transmitted disease Biological Sciences Heptoses pathogen-associated molecular pattern Neisseria gonorrhoeae unclassified drug Toll-Like Receptor 5 chemistry inflammation HIV-1 Female Bacterial outer membrane mutagenesis microbial-associated molecular pattern |
| Zdroj: | Proceedings of the National Academy of Sciences of the United States of America. 110(25) |
| ISSN: | 1091-6490 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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