Dataset Information

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.

SUBMITTER: Zhang J

PROVIDER: S-EPMC9204526 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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

Zhang Jingyun J Peng Jingwen J Li Dongmei D Mei Huan H Yu Yu Y Li Xiaofang X She Xiaodong X Liu Weida W

Frontiers in immunology 20220526

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 ...[more]

PMID: 35720274

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Project description:Vulvovaginal candidiasis (VVC) can alter the vaginal microbiome composition and structure, and this may be correlated with its variable treatment efficacy. Integrated analysis of the mycobiome and bacteriome in VVC could facilitate accurate diagnosis of infected patients and further decipher the characterized bacteriome in different types of VVC. Our mycobiome analysis determined two common types of VVC, which were clustered into two community state types (CSTs) featured by Candida glabrata (CST I) and Candida albicans (CST II). Subsequently, we compared the vaginal bacteriome in two CSTs of VVC and two other types of reproductive tract infections (RTIs), bacterial vaginosis (BV) and Ureaplasma urealyticum (UU) infection. The vaginal bacteriome in VVC patients was between the healthy and other RTIs (BV and UU) status, it bore the greatest resemblance to that of healthy subjects. While BV and UU patients have the unique vaginal microbiota community structure, which very different with healthy women. Compared with CST II, the vaginal bacteriome of CST I VVC was characterized by Prevotella, a key signature in BV. In comparison, CST II was featured by Ureaplasma, the pathogen of UU. The findings of our study highlight the need for co-analysis and simultaneous consideration of vaginal mycobiome and bacteriome in the diagnosis and treatment of VVC to solve common clinical problems, such as unsatisfactory cure rates and recurrent symptoms. IMPORTANCE Fungi headed by C. albicans play a critical role in VVC but are not sufficient for its occurrence, indicating the involvement of other factors, such as the vaginal bacteriome. We found that different CST correspond to different bacterial composition in patients with VVC, and this could underlie the alteration of vaginal microorganism environment in VVC patients. We believe that this correlation should not be ignored, and it may be related to the unsatisfactory treatment outcomes and high recurrence rate of VVC. Here, we provided evidence for associations between vaginal bacteriome patterns and fungal infection. Screening specific biomarkers for three common RTIs paves a theoretical basis for further development of personalized precision treatment.

Project description:Despite the strikingly high worldwide prevalence of vulvovaginal candidiasis (VVC), treatment options for recurrent VVC (RVVC) remain limited, with many women experiencing failed clinical treatment with frontline azoles. Further, the cause of onset and recurrence of disease is largely unknown, with few studies identifying potential mechanisms of treatment failure. This study aimed to assess a panel of clinical samples from healthy women and those with RVVC to investigate the influence of Candida, the vaginal microbiome, and how their interaction influences disease pathology. 16S rRNA sequencing characterized disease by a reduction in specific health-associated Lactobacillus species, such as Lactobacillus crispatus, coupled with an increase in Lactobacillus iners. In vitro analysis showed that Candida albicans clinical isolates are capable of heterogeneous biofilm formation, and we found the presence of hyphae and C. albicans aggregates in vaginal lavage fluid. Additionally, the ability of Lactobacillus to inhibit C. albicans biofilm formation and biofilm-related gene expression was demonstrated. Using RNA sequencing technology, we were able to identify a possible mechanism by which L. crispatus may contribute to re-establishing a healthy vaginal environment through amino acid acquisition from C. albicans. This study highlights the potential formation and impact of Candida biofilms in RVVC. Additionally, it suggests that RVVC is not entirely due to an arbitrary switch in C. albicans from commensal to pathogen and that understanding interactions between this yeast and vaginal Lactobacillus species may be crucial to elucidating the cause of RVVC and developing appropriate therapies. IMPORTANCE RVVC is a significant burden, both economically and for women's health, but its prevalence is poorly documented globally due to the levels of self-treatment. Identifying triggers for development and recurrence of VVC and the pathogenesis of the microbes involved could considerably improve prevention and treatment options for women with recurrent, azole-resistant cases. This study therefore aimed to examine the interkingdom dynamics from healthy women and those with RVVC using next-generation sequencing techniques and to further investigate the molecular interactions between C. albicans and L. crispatus in a relevant biofilm coculture system.

Dataset Information

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

Publications

Divergent EGFR/MAPK-Mediated Immune Responses to Clinical <i>Candida</i> Pathogens in Vulvovaginal Candidiasis.

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