A systems genomics approach identifies <i>SIGLEC15</i> as a susceptibility factor in recurrent vulvovaginal candidiasis.

Abstract

<i>Candida</i> vaginitis is a frequent clinical diagnosis with up to 8% of women experiencing recurrent vulvovaginal candidiasis (RVVC) globally. RVVC is characterized by at least three episodes per year. Most patients with RVVC lack known risk factors, suggesting a role for genetic risk factors in this condition. Through integration of genomic approaches and immunological studies in two independent cohorts of patients with RVVC and healthy individuals, we identified genes and cellular processes that contribute to the pathogenesis of RVVC, including cellular morphogenesis and metabolism, and cellular adhesion. We further identified <i>SIGLEC15</i>, a lectin expressed by various immune cells that binds sialic acid-containing structures, as a candidate gene involved in RVVC susceptibility. <i>Candida</i> stimulation induced <i>SIGLEC15</i> expression in human peripheral blood mononuclear cells (PBMCs) and a polymorphism in the <i>SIGLEC15</i> gene that was associated with RVVC in the patient cohorts led to an altered cytokine profile after PBMC stimulation. The same polymorphism led to an increase in <i>IL1B</i> and <i>NLRP3</i> expression after <i>Candida</i> stimulation in HeLa cells in vitro. Last, <i>Siglec15</i> expression was induced by <i>Candida</i> at the vaginal surface of mice, where in vivo silencing of <i>Siglec15</i> led to an increase in the fungal burden. <i>Siglec15</i> silencing was additionally accompanied by an increase in polymorphonuclear leukocytes during the course of infection. Identification of these pathways and cellular processes contributes to a better understanding of RVVC and may open new therapeutic avenues.