Abstract
<title>Abstract</title> <p> Vulvovaginal candidiasis (VVC) is a mucosal yeast infection that affects most women at least once in their lifetime, and exhibits severe recurrence (RVVC) in a subset of patients. The onset of (R)VVC is linked to a complex interplay between fungal pathogenicity and excessive innate immune responses driving neutrophilic inflammation that mediates disease progression. The current state of knowledge of VVC pathogenesis is established based on patient studies, animal models, and <italic>in vitro</italic> cell culture models. Conventional monolayer epithelial infection models cannot simulate recruitment of inflammatory neutrophils, a hallmark of VVC pathogenesis, whereas murine animal models exhibit some interspecies differences in the immune system. Recent advances in microfluidic organ-on-chip systems enabled us to establish a vulvovaginal-candidiasis (VVC)-on-chip model that simulates infection of vaginal mucosa by <italic>Candida albicans</italic> and can be used to study innate immune responses driving neutrophil-mediated inflammation. <italic>C. albicans</italic> infection elicits proinflammatory responses that induce neutrophil recruitment to the vaginal epithelium in the chip. Neutrophils were found to swarm towards sites of <italic>C. albicans-</italic> infected epithelium, which was visualized and quantified <italic>via</italic> 3D object-based segmentation analysis. While recruited neutrophils fail to fully clear the infection, they exacerbate proinflammatory cytokine responses, consistent with clinical observations. Overall, this VVC-on-chip model represents a novel tool to dissect mechanisms driving the immunopathology of VVC. Moreover, it also provides a platform for studying host-pathogen interactions at the vaginal epithelial interface as well as evaluation of both pathogen- and host-directed therapies. </p>