Divergent EGFR/MAPK-Mediated Immune Responses to Clinical Candida Pathogens in Vulvovaginal Candidiasis

Abstract

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 mucosa after C. albicans exposure, but whether this pathway plays a similar response in vaginal epithelial cells is not known. Here, we observed that phosphorylation of EGFR and p38 was continuously activated in vaginal epithelial cells by C. albicans strain SC5314. This differs markedly from oral epithelial cells, which respond in a biphasic manner in order to properly 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 trigger higher levels of phosphorylated ERK1/2 and c-Fos than C. albicans. Inhibition of EGFR significantly reduces inflammatory response and epithelial damage induced by C. albicans both in vitro and in vivo, while inhibition of p38 leads to significant repair of epithelial damage triggered by both C. albicans and NAC species. 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.

The Interplay between Candida albicans, Vaginal Mucosa, Host Immunity and Resident Microbiota in Health and Disease: An Overview and Future Perspectives

“…The initial interaction between the fungus and the vaginal epithelium is mediated by passive forces, i.e., van der Waals forces and hydrophobic interactions. Subsequently, the adhesion is strengthened and stabilized by the binding of the fungal adhesins with specific surface epithelial cell receptors and host extracellular matrix components [ 19 , 20 , 22 ]. To facilitate its adhesion to the receptors, C. albicans possesses a large variety of adhesins, including the agglutinin-like sequence (Als) protein family, which are well characterized.…”

Does Candida auris colonize the oral cavity? A retrospective institutional experience

“…Beginning in 2018, C. auris has been mandated to be reported in the United States (CSTE, 2018). To date, C. auris isolates have been recovered from several head and neck mucosal sites (ocular, nasal, pharynx, tracheal), as summarized in Table 1, as well as blood, sputum, pus, urine, skin, abdominal and pleural fluid, and other mucosa (rectal, vulvovaginal, urinary tract) (Khan et al, 2018; Nobrega de Almeida Jr et al, 2021; Piatti et al, 2022; Zhang et al, 2022). Although C. auris has not been reported to colonize oral mucosal surfaces, it is not clear whether its presence was actively screened for in the oral cavity.…”

“…In contrast to other Candida species, C. auris persistently colonizes the skin and nosocomial surfaces and demonstrates the capacity to resist common disinfectants and to spread rapidly among patients (Kordalewska & Perlin, 2019;Welsh et al, 2017). Most concerning, C. auris exhibits a high level of resistance to multiple drug classes and misidentification by available commercial laboratory studies has complicated its clinical management (Kordalewska & Perlin, 2019 (Khan et al, 2018;Nobrega de Almeida Jr et al, 2021;Piatti et al, 2022;Zhang et al, 2022). Although C. auris has not been reported to colonize oral mucosal surfaces, it is not clear whether its presence was actively screened for in the oral cavity.…”