The Story behind the Science: Solving the riddle for the pathogenesis of vulvovaginal candidiasis

ABSTRACT For nearly three decades, the pathogenesis of vulvovaginal candidiasis (VVC) remained an enigma. During the HIV/AIDS epidemic, observations that women with profound CD4 + T-cell deficiencies were not more susceptible to VVC challenged the prevailing assumption that protective adaptive immunity dictated all mucosal Candida infections. Here, we recount the scientific journey and trajectory that began with these observations and culminated in a paradigm shift in understanding VVC pathogenesis. Through extensive clinical studies, animal models, and a groundbreaking live Candida challenge clinical study, VVC was ultimately redefined as an immunopathogenic condition characterized by a robust yet dysfunctional neutrophil response to C. albicans within the vaginal environment. We highlight the key discoveries, challenges, and experiences that reshaped the field and finally solved the long-standing riddle of VVC pathogenesis.