The microbiota in the female genital tract is an intricate assembly of diverse aerobic, anaerobic, and microaerophilic microorganisms, which share the space within the reproductive tract and engage in complex interactions. Microbiome dysbiosis may disrupt the symbiotic relationship between the host and microorganisms and play a pivotal role in the pathogenesis of various diseases, including its involvement in the establishment of human papillomavirus (HPV)-associated cervical cancer (CC). Interventions to restore microbiota homeostasis (e.g., probiotics) and bacterial-vector HPV therapeutic vaccines have been reported to be potentially effective in clearing HPV infection and ameliorating cytological abnormalities. In this review, we place emphasis on elucidating the alterations within the cervical-vaginal microbiota as well as the intratumoral microbiota in the context of high-risk HPV (HR-HPV) infection and its subsequent progression to cervical intraepithelial neoplasia/CC. Furthermore, we explore the mechanisms by which these microbial communities exert potential pathogenic or protective effects, including modulating genital inflammation and immune responses, affecting HR-HPV oncogene expression and oncoprotein production, regulating oxidative stress and deoxyribonucleic acid (DNA) damage, and inducing metabolic rewiring. Lastly, we summarize the latest evidence in human trials regarding the efficacy of probiotics, prebiotics and probiotic-vector HPV therapeutic vaccines. This review aims to foster a deeper understanding of the role of the microbiota in HR-HPV infection-related cervix cancer development, and further provide a theoretical basis for the development of preventive and therapeutic strategies based on microbial modulation.

Candida parapsilosis is becoming a predominant non-albicans cause of invasive candidiasis (IC). Echinocandins are the preferred choice for IC treatment and prophylaxis. Resistance to echinocandins in C. parapsilosis has emerged in several countries, but little is known about the susceptibility profile in China or about mechanisms of resistance. Here, we investigated the echinocandin susceptibilities of 2523 C. parapsilosis isolates collected from China and further explored the resistance mechanism among echinocandin-resistant isolates. Anidulafungin exhibited the highest MICs (MIC_50/90, 1 and 2 µg/mL; GM, 0.948 µg/mL), while caspofungin showed better activity (0.5 and 1 µg/mL; 0.498 µg/mL). Significantly higher echinocandin MICs were observed among blood-derived isolates compared to others, especially for caspofungin (GM, 1.348 µg/mL vs 0.478 µg/mL). Isolates from ICU and surgical wards also showed higher MICs. Twenty isolates showed intermediate phenotypes for at least one echinocandin. One was resistant to all three echinocandins, fluconazole and voriconazole, which caused breakthrough IC during long-term exposure to micafungin. WGS revealed this isolate carried a mutation S656P in hotspot1 region of Fks1. Bioinformatics analyses suggested that this mutation might lead to an altered protein conformation. CRISPR Cas9-mediated introduction of this mutation into a reference C. parapsilosis strain increased MICs of all echinocandins 64-fold, with similar results found in the subspecies, C. orthopsilosis and C. metapsilosis. This is the first report of a multi-azole resistant and pan-echinocandin resistant C. parapsilosis isolate, and the identification of a FKS1^S656P conferring pan-echinocandin resistance. Our study underscores the necessity of rigorous management of antifungal use and of monitoring for fungal susceptibility.

Candida parapsilosis is an important species causing invasive candidiasis (IC) in China. The present survey was a national multicenter study of the molecular epidemiology and antifungal susceptibility profiles of C. parapsilosis. Non-duplicate C. parapsilosis isolates were collected from 10 hospitals across China in the CHIF-NET program 2016–2017. Isolates were genotyped using four highly polymorphic microsatellite markers, and susceptibility profiles determined using Sensititre YeastOne^TM YO10. A total of 319 C. parapsilosis from separate patients with IC were studied; 49.2, 17.9, and 10.3% isolates were from patients in surgical departments, general intensive care units (ICUs) and neonatal ICUs (NICU), respectively. C. parapsilosis showed good susceptibility to nine antifungal drugs. Microsatellite analysis identified 122 microsatellite (MT) types. Most MT types had sporadic distribution. However, we identified 32 clusters across 10 hospitals; seven clusters were caused by seven endemic genotypes involving five or more isolates in hospitals designated as H01, H02, H06, and H10. These clusters mainly affected surgical departments and ICUs, except for genotype MT42 which was seen in 22 patients from NICU (hospital H06). Of 16 fluconazole-resistant isolates, seven from hospital H02 shared the same genotype MT70, and three from hospital H04 were of genotype MT47. For 37 isolates with non-wild type MICs to 5-flucytosine, 29 were from hospital H01 (genotype MT48). Here we present the first nationwide molecular epidemiology study of C. parapsilosis in China, identified several previously unrecognized clusters, which included antifungal drug resistant isolates. These findings provide important data for control of IC in China.

SUMMARY: Vulvovaginal candidiasis (VVC) is a prevalent global health burden, particularly among reproductive-aged women. Recurrent VVC affects a significant proportion of this population, presenting therapeutic challenges. The predominant pathogen, Candida albicans , opportunistically transitions from a commensal organism to a pathogen when microenvironmental conditions become dysregulated. Recently, non- albicans Candida species have gained attention for their reduced antifungal susceptibility and recurrence tendencies. Diagnosis is constrained by the limitations of conventional microbiological techniques, while emerging molecular assays offer enhanced pathogen detection yet lack established thresholds to differentiate between commensal and pathogenic states. Increasing resistance issues are encountered by traditional azole-based antifungals, necessitating innovative approaches that integrate microbiota modulation and precision medicine. Therefore, this review aims to systematically explore the pathogenic diversity, drug resistance mechanisms, and biofilm effects of Candida species. Vaginal microbiota (VMB) alterations associated with VVC were also examined, focusing on the interaction between Lactobacillus spp. and pathogenic fungi, emphasizing the role of microbial dysbiosis in disease progression. Finally, the potential therapeutic approaches for VVC were summarized, with a particular focus on the use of probiotics to modulate the VMB composition and restore a healthy microbial ecosystem as a promising treatment strategy. This review addresses antifungal resistance and adopts a microbiota-centric approach, proposing a comprehensive framework for personalized VVC management to reduce recurrence and improve patient outcomes.

Cryptococcus species are opportunistic human fungal pathogens. Survival in a hostile environment, such as the elevated body temperatures of transmitting animals and humans, is crucial for Cryptococcus infection. Numerous intriguing investigations have shown that the Hsf family of thermotolerance transcription regulators plays a crucial role in the pathogen-host axis of Cryptococcus. Although Hsf1 is known to be a master regulator of the heat shock response through the activation of gene expression of heat shock proteins (Hsps). Hsf1 and other Hsfs are multifaceted transcription regulators that regulate the expression of genes involved in protein chaperones, metabolism, cell signal transduction, and the electron transfer chain. In Saccharomyces cerevisiae, a model organism, Hsf1’s working mechanism has been intensively examined. Nonetheless, the link between Hsfs and Cryptococcus pathogenicity remains poorly understood. This review will focus on the transcriptional regulation of Hsf function in Cryptococcus, as well as potential antifungal treatments targeting Hsf proteins.