Lactic acid in the vaginal milieu modulates the <i>Candida</i>-host interaction

Vulvovaginal candidiasis (VVC) is one of the most common infections caused by <i>Candida albicans</i>. VVC is characterized by an inadequate hyperinflammatory response and clinical symptoms associated with <i>Candida</i> colonization of the vaginal mucosa. Compared to other host niches in which <i>C. albicans</i> can cause infection, the vaginal environment is extremely rich in lactic acid that is produced by the vaginal microbiota. We examined how lactic acid abundance in the vaginal niche impacts the interaction between <i>C. albicans</i> and the human immune system using an <i>in vitro</i> culture in vaginal simulative medium (VSM). The presence of lactic acid in VSM (VSM+LA) increased <i>C. albicans</i> proliferation, hyphal length, and its ability to cause damage during subsequent infection of vaginal epithelial cells. The cell wall of <i>C. albicans</i> cells grown in VSM+LA displayed a robust mannan fibrillar structure, β-glucan exposure, and low chitin content. These cell wall changes were associated with altered immune responses and an increased ability of the fungus to induce trained immunity. Neutrophils were compromised in clearing <i>C. albicans</i> grown in VSM+LA conditions, despite mounting stronger oxidative responses. Collectively, we found that fungal adaptation to lactic acid in a vaginal simulative context increases its immunogenicity favouring a pro-inflammatory state. This potentially contributes to the immune response dysregulation and neutrophil recruitment observed during recurrent VVC.外阴阴道假丝酵母菌病（Vulvovaginal candidiasis, VVC）是由白假丝酵母菌（Candida albicans）引发的最常见感染性疾病之一。VVC以异常的过度炎症反应，以及伴随念珠菌属（Candida）在阴道黏膜定植的临床症状为特征。相较于其他可被白假丝酵母菌（C. albicans）感染的宿主微环境，阴道环境中富含由阴道微生物群产生的乳酸。本研究借助阴道模拟培养基（Vaginal simulative medium, VSM）构建体外（in vitro）培养模型，探究阴道微环境内的乳酸丰度如何影响白假丝酵母菌与人体免疫系统的相互作用。在VSM中添加乳酸（VSM+LA）可促进白假丝酵母菌的增殖、延长菌丝长度，并增强其在后续感染阴道上皮细胞时的损伤能力。在VSM+LA环境中培养的白假丝酵母菌，其细胞壁展现出显著的甘露聚糖纤维状结构、β-葡聚糖暴露水平提升，且几丁质含量降低。上述细胞壁结构改变与免疫应答调控异常相关，同时增强了该真菌诱导训练免疫（trained immunity）的能力。尽管中性粒细胞会产生更强的氧化应答，但其对VSM+LA环境中培养的白假丝酵母菌的清除能力却受到削弱。综上，本研究发现，在阴道模拟环境中，真菌对乳酸的适应性增强了其免疫原性，偏向促炎状态。这一现象可能与复发性外阴阴道假丝酵母菌病中观察到的免疫应答失调及中性粒细胞招募异常相关。