Protective role of type I interferons in vulvovaginal candidiasis

RODRIGUEZ, EMILSE; ANGIOLINI, SOFÍA CARLA; MIRÓ, MARÍA SOLEDAD; VIGEZZI, CECILIA; ICELY, PAULA ALEJANDRA; RIERA, FERNANDO OSCAR; CAEIRO, JUAN PABLO; SOTOMAYOR, CLAUDIA ELENA

Salvador de Bahia

Congreso; 17th INFOCUS-1st ISHAM Latin American Congress; 2019

Type I interferons (IFNs-I) have been traditionally associated with antiviral immune responses, however, their importance in host defence against fungal pathogens is being increasingly appreciated. C. albicans (Ca) is the main causative agent of Vulvovaginal Candidiasis (VVC), an inflammatory disease affecting 75% of healthy women in reproductive age at least once in their lifetime. Objective: This study aimed to determine whether Ca immune recognition triggers IFNs-I pathway in epithelial cells of the female genital tract (FGT) and its ability to modulate the local immune response during VVC development.Methods: We carried out two experimental strategies with: a) FGT cell line and b) mice model of VVC. a) Human cervical epithelial cell line (HeLa) was stimulated in vitro with viable Ca-SC5314 (5:1 ratio); Heat-Killed-Ca; Ca-FKS1.S645P (-glucan defective strain); Curdlan (-(1,3)-glucan, Dectin-1 agonist) and LPS (control) during 4h. IFNβ, IRF3 and IRF7 (molecules associated with IFNs-I signature) mRNA levels were measured by qPCR.b) Female C57BL/6 (WT) and IFN-α/β receptor 1 deficient (IFNAR-/-) mice on pseudo estrus phase (estradiol-treated) were inoculated intravaginally with 5x106 blastospores of Ca. The pattern of susceptibility to infection was evaluated in terms of local fungal burden in vaginal lavages (VL) obtained at day (D) 1, 2, 4 and 8 post infection (pi). Pro and anti-inflammatory cytokines (ELISA) as well also polymorphonuclear cells (PMNs) recruitment were determined in VL. Histological studies were performed in mice vaginas.Results: The results obtained with the in vitro model showed that yeast-to-hypha switch of Ca and the exposure of -glucan in the fungal wall were able to activate IFNs-I pathway in epithelial cells of the FGT showing strong induction of IFNβ and IRF7mRNA (p<0.01).In vivo results demonstrated that the absence of IFNAR-mediated signalling predisposes to an increased initial vaginal fungal burden (D1) (WT p<0.05). The epithelial invasion by Ca, which is the fact that finally leads to cell damage and the activation of host immune response was evaluated by histological scores. Mice vaginas showed an initial massive Ca hyphae penetration to epithelium and Invasiveness-Score was higher in IFNAR-/- mice compared to WT (D1 and D2 p<0.05). A strong local inflammatory reaction characterized by the presence of large intraepithelial abscesses were observed in IFNAR-/- and Inflammation-Score reach significant values compared to WT (D2, p<0.001). PMNs recruitment in VL showed increased values at D8 of infection in absence of IFNs-I signalling (p<0.001). Local cytokine balance was modified and IL-1β was lower in IFNAR -/- compared to WT animals (D2, D4p<0.001) meanwhile TGF was increased (D4, D8<0.05).Conclusion: Taken together, our results demonstrate that epithelial cells of the FGT are capable to activate IFNs-I pathway in response to Ca and that these cytokines play an important role in the initial control of local fungal burden, the invasiveness of Ca on the vaginal epithelium, the inflammatory response on the tissue and the local cytokine balance in the vaginal lumen. These in vivo results suggest an early protective role for IFNs-I on VVC.