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.

Bottlenecks in HIV-1 transmission: insights from the study of founder viruses

“…For example, confection with Neisseria gonorrhoeae is associated with elevated concentrations of HIV-1 in the blood plasma of women 56 and in semen 57 . N. gonorrhoeae produces heptose monophosphate, which stimulates an innate immune response that results in increased nuclear factor-κB (NF-κB)-mediated transcription of the HIV-1 long terminal repeats (LTR) 58 as one mechanism that could affect the level of virus. Similarly, co-infection with herpes simplex virus 2 (HSV-2) has also been associated with elevated concentrations of HIV-1 in genital secretions (reviewed in REF.…”

Sexual Positioning Among Men Who Have Sex With Men: A Narrative Review

“…Similarly, gonorrhea cases among MSM increased 14% compared to the cases among men who have sex with women only that remained stable and the proportion of cases among women that declined 13% (Kidd, Stenger, Kirkcaldy, Llata, & Weinstock, 2015). Data further show that STIs potentiate HIV acquisition and transmission (Dallabetta & Neilsen, 2005; Frye et al, 2009; Malott et al, 2013). Both RAI and IAI, as sexual positioning practices, can facilitate HIV acquisition and transmission among MSM.…”

Interplay between viruses and bacterial microbiota in cancer development

“…Ferreira et al found that stimulation of HIV infected T-cells with TLR3, 4, or 5 ligands leads to enhanced HIV-1 replication via direct activation of HIV long terminal repeats, or by inducing secreted factors that promote HIV replication [109]. Among the pathogens suspected to contribute to HIV infection and reactivation, one player stands out - Neisseria gonorrhoeae : it was found to be highly associated with HIV infection [110] and activation of HIV expression [109,111,112]. Not only does N. gonorrhoeae drives an increase of activated CD4+ T-cells [111] and pro-inflammatory cytokines in genital epithelial cells such as IL-6, IL-8 and TNFα [109], but exposure to the pathogen directly drives HIV expression in T cells in NF-kB and AP-1 dependent manner [109,111].…”

“…Among the pathogens suspected to contribute to HIV infection and reactivation, one player stands out - Neisseria gonorrhoeae : it was found to be highly associated with HIV infection [110] and activation of HIV expression [109,111,112]. Not only does N. gonorrhoeae drives an increase of activated CD4+ T-cells [111] and pro-inflammatory cytokines in genital epithelial cells such as IL-6, IL-8 and TNFα [109], but exposure to the pathogen directly drives HIV expression in T cells in NF-kB and AP-1 dependent manner [109,111]. Malott et al showed that N. gonorrhoeae by-product heptose-monophosphate is necessary for invoking these host responses [111] (Fig.…”

“…Not only does N. gonorrhoeae drives an increase of activated CD4+ T-cells [111] and pro-inflammatory cytokines in genital epithelial cells such as IL-6, IL-8 and TNFα [109], but exposure to the pathogen directly drives HIV expression in T cells in NF-kB and AP-1 dependent manner [109,111]. Malott et al showed that N. gonorrhoeae by-product heptose-monophosphate is necessary for invoking these host responses [111] (Fig. 3C).…”