Abstract
Inflammation in the female reproductive tract (FRT) is associated with increased HIV transmission. Lactobacillus spp. dominate the vaginal microbiota of many women and their presence is associated with reduced HIV acquisition. Here we demonstrate that lactic acid (LA), a major organic acid metabolite produced by lactobacilli, mediates anti-inflammatory effects on human cervicovaginal epithelial cells. Treatment of human vaginal and cervical epithelial cell lines with LA (pH 3.9) elicited significant increases in the production of the anti-inflammatory cytokine IL-1RA. When added simultaneously or prior to stimulation, LA inhibited the Toll-like receptor agonist-elicited production of inflammatory mediators IL-6, IL-8, TNFα, RANTES, and MIP3α from epithelial cell lines and prevented IL-6 and IL-8 production by seminal plasma. The anti-inflammatory effect of LA was mediated by the protonated form present at pH≤3.86 and was observed with both L- and D-isomers. A similar anti-inflammatory effect of LA was observed in primary cervicovaginal cells and in an organotypic epithelial tissue model. These findings identify a novel property of LA that acts directly on epithelial cells to inhibit FRT inflammation and highlights the potential use of LA-containing agents in the lower FRT as adjuncts to female-initiated strategies to reduce HIV acquisition.
Highlights
Curbing the HIV epidemic will require effective methods to reduce HIV acquisition in women, who represent almost half the global HIV burden of 37 million infected individuals[1] and are eight times more likely than men to acquire HIV following vaginal intercourse.[2]
Studies of the vaginal microbiota of women in Africa have demonstrated that high-diversity bacterial communities lacking Lactobacillus spp., such as those found in bacterial vaginosis (BV), are associated with increased levels of pro-inflammatory mediators in the FRT10–13 and increased risk of HIV acquisition,[14] with a recent study reporting a greater than fourfold increased risk of HIV
Cervicovaginal epithelial cells cultured in transwells remain viable in the presence of physiological concentrations of lactic acid (LA) The average physiological LA concentration in the vaginal lumen of women with lactobacillus-dominated microbiota is 1.0±0.2% (w/v) and the vaginal pH ranges from 2.8 to 4.2.26 the presence of mucus and the stratified structure of the vaginal epithelium, that includes surface layers of flattened dead cells,[27] means that viable cells within the basal layers of the epithelium are likely exposed to LA concentrations o1%
Summary
Curbing the HIV epidemic will require effective methods to reduce HIV acquisition in women, who represent almost half the global HIV burden of 37 million infected individuals[1] and are eight times more likely than men to acquire HIV following vaginal intercourse.[2] The female reproductive tract (FRT) contains numerous structural, environmental, and immunological barriers to HIV infection.[3] the importance of the vaginal microbiota and the role of their organic acid metabolites in influencing HIV transmission through immunomodulatory effects on the FRT mucosa remain largely unknown. The vaginal microbiota of asymptomatic women of reproductive age is generally dominated by Lactobacillus spp.,[4] which is associated with reduced susceptibility to HIV and other sexually transmitted infections (STIs).[5,6] In contrast, microbial dysbioses such as bacterial vaginosis (BV) are associated with a decreased prevalence of lactobacilli and an increase in highdiversity bacterial communities comprising strict or facultative anaerobes including Gardnerella, Prevotella, and Atopobium (reviewed in Aldunate et al.[3]). BV is associated with a more than threefold increased risk of HIV acquisition,[7] whereas
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