S7.2d Divergent EGFR/MAPK-mediated immune responses to clinical Candida pathogens in vulvovaginal candidiasis

Abstract S7.2 More than just candidemia: clinical aspects, diagnosis and treatment, and pathogenesis of deep-seated candidiasis, September 23, 2022, 10:30 AM - 12:00 PM Objectives Vulvovaginal candidiasis (VVC) is characterized by symptomatic inflammatory responses in the vagina caused by Candida albicans and non-albicans Candida (NAC) species. The epidermal growth factor receptor (EGFR) -mitogen-activated protein kinase (MAPK) signaling pathway has been linked to immune responses of oral epithelial cells upon C. albicans exposure, but whether this pathway plays a similar response in vaginal epithelial cells is not determined. Methods The activation of EGFR and MAPK signaling pathways in vaginal epithelial cells infected with C. albicans was determined by RNA sequencing and Western blot. The relationship between EGFR and MAPK signaling was verified via inhibition of EGFR and construction of EGFR-overexpressing cells. Enzyme-linked immunosorbent assay (ELISA) and Real Time Cellular Analysis (RTCA) techniques were used to detect the effect of EGFR-MAPK signaling pathway on regulating the secretion of inflammatory cytokines and cell damage induced by C. albicans. The mouse model of VVC infected by C. albicans was constructed, and the role of EGFR signaling pathway in regulating fungal burden, vaginal inflammation, and epithelial damage was determined by Periodic Acid-Schiff stain and immunofluorescence. Results We observed that phosphorylation of EGFR and p38 was continuously activated in vaginal epithelial cells by C. albicans strain SC5314. The response is not in a biphasic manner that is critical for oral epithelial cells to discriminate the morphology of C. albicans. When compared with SC5314, a highly azole-resistant C. albicans isolate 1052 can induce a stronger phosphorylated signal of EGFR and p38, while clinically-isolated NAC strains including C. tropicalis, C. glabrata, C. parapsilosis, and C. auris triggered higher levels of phosphorylated ERK1/2 and c-Fos than C. albicans. Consistently, inhibition of EGFR significantly reduced inflammatory response and epithelial damage induced by C. albicans in vitro and in vivo, while inhibition of p38 led to great loss of epithelial damage triggered by both C. albicans and NAC species. Conclusion These results confirm the importance of the EGFR-MAPK signaling in VVC pathogenesis and highlight the remarkable immunogenic differences between C. albicans and NAC species in host-microbe interactions.