|
1
|
Liu Z, Yang H, Huang R, Li X, Sun T, Zhu L. Vaginal mycobiome characteristics and therapeutic strategies in vulvovaginal candidiasis (VVC): differentiating pathogenic species and microecological features for stratified treatment. Clin Microbiol Rev 2025:e0028424. [PMID: 40261031 DOI: 10.1128/cmr.00284-24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/24/2025] Open
Abstract
SUMMARYVulvovaginal 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.
Collapse
Affiliation(s)
- Zimo Liu
- Department of Obstetrics and Gynecology, National Clinical Research Center for Obstetric & Gynecologic Diseases, State Key Laboratory of Common Mechanism Research for Major Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- State Key Laboratory of Complex, Severe, and Rare Diseases, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
| | - Hua Yang
- Department of Obstetrics and Gynecology, National Clinical Research Center for Obstetric & Gynecologic Diseases, State Key Laboratory of Common Mechanism Research for Major Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Roujie Huang
- Department of Obstetrics and Gynecology, National Clinical Research Center for Obstetric & Gynecologic Diseases, State Key Laboratory of Common Mechanism Research for Major Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- State Key Laboratory of Complex, Severe, and Rare Diseases, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
| | - Xiaochuan Li
- Department of Obstetrics and Gynecology, National Clinical Research Center for Obstetric & Gynecologic Diseases, State Key Laboratory of Common Mechanism Research for Major Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Tianshu Sun
- Department of Obstetrics and Gynecology, National Clinical Research Center for Obstetric & Gynecologic Diseases, State Key Laboratory of Common Mechanism Research for Major Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- State Key Laboratory of Complex, Severe, and Rare Diseases, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
- Clinical Biobank, Center for Biomedical Technology, Institute of Clinical Medicine, National Science and Technology Key Infrastructure on Translational Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Lan Zhu
- Department of Obstetrics and Gynecology, National Clinical Research Center for Obstetric & Gynecologic Diseases, State Key Laboratory of Common Mechanism Research for Major Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- State Key Laboratory of Complex, Severe, and Rare Diseases, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
| |
Collapse
|
|
2
|
Gaffar NR, Valand N, Venkatraman Girija U. Candidiasis: Insights into Virulence Factors, Complement Evasion and Antifungal Drug Resistance. Microorganisms 2025; 13:272. [PMID: 40005639 PMCID: PMC11858274 DOI: 10.3390/microorganisms13020272] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2024] [Revised: 01/23/2025] [Accepted: 01/24/2025] [Indexed: 02/27/2025] Open
Abstract
Invasive fungal infections constitute a substantial global health burden, with invasive candidiasis representing approximately 70% of reported cases worldwide. The emergence of antifungal resistance among Candida species has further exacerbated this challenge to healthcare systems. Recent epidemiological studies have documented a concerning shift towards non-albicans Candida species, exhibiting reduced antifungal susceptibility, in invasive candidiasis cases. The complement system serves as a crucial first-line defence mechanism against Candida infections. These fungal pathogens can activate the complement cascade through three conventional pathways-classical, lectin, and alternative-in addition to activation through the coagulation system. While these pathways are initiated by distinct molecular triggers, they converge at C3 convertase formation, ultimately generating biologically active products and the membrane attack complex. Candida species have evolved sophisticated mechanisms to evade complement-mediated host defence, including the masking of cell wall components, proteolytic cleavage and inhibition of complement proteins, recruitment of complement regulators, and acquisition of host proteins. This review examines the intricate interplay between Candida species and the host complement system, with emphasis on complement evasion strategies. Furthermore, we highlight the importance of exploring the crosstalk between antifungal resistance and immune evasion strategies employed by Candida species. Understanding these interactions may facilitate the development of novel therapeutic approaches and strategies to overcome treatment failures in Candida species infections.
Collapse
Affiliation(s)
| | | | - Umakhanth Venkatraman Girija
- Leicester School of Allied Health Sciences, Faculty of Health & Life Sciences, De Montfort University, Leicester LE1 9BH, UK
| |
Collapse
|
|
3
|
Weerasinghe H, Stölting H, Rose AJ, Traven A. Metabolic homeostasis in fungal infections from the perspective of pathogens, immune cells, and whole-body systems. Microbiol Mol Biol Rev 2024; 88:e0017122. [PMID: 39230301 PMCID: PMC11426019 DOI: 10.1128/mmbr.00171-22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/05/2024] Open
Abstract
SUMMARYThe ability to overcome metabolic stress is a major determinant of outcomes during infections. Pathogens face nutrient and oxygen deprivation in host niches and during their encounter with immune cells. Immune cells require metabolic adaptations for producing antimicrobial compounds and mounting antifungal inflammation. Infection also triggers systemic changes in organ metabolism and energy expenditure that range from an enhanced metabolism to produce energy for a robust immune response to reduced metabolism as infection progresses, which coincides with immune and organ dysfunction. Competition for energy and nutrients between hosts and pathogens means that successful survival and recovery from an infection require a balance between elimination of the pathogen by the immune systems (resistance), and doing so with minimal damage to host tissues and organs (tolerance). Here, we discuss our current knowledge of pathogen, immune cell and systemic metabolism in fungal infections, and the impact of metabolic disorders, such as obesity and diabetes. We put forward the idea that, while our knowledge of the use of metabolic regulation for fungal proliferation and antifungal immune responses (i.e., resistance) has been growing over the years, we also need to study the metabolic mechanisms that control tolerance of fungal pathogens. A comprehensive understanding of how to balance resistance and tolerance by metabolic interventions may provide insights into therapeutic strategies that could be used adjunctly with antifungal drugs to improve patient outcomes.
Collapse
Affiliation(s)
- Harshini Weerasinghe
- Department of Biochemistry and Molecular Biology and the Infection Program, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia
- Centre to Impact AMR, Monash University, Clayton, Victoria, Australia
| | - Helen Stölting
- Department of Biochemistry and Molecular Biology and the Metabolism, Diabetes and Obesity Program, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia
| | - Adam J Rose
- Department of Biochemistry and Molecular Biology and the Metabolism, Diabetes and Obesity Program, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia
| | - Ana Traven
- Department of Biochemistry and Molecular Biology and the Infection Program, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia
- Centre to Impact AMR, Monash University, Clayton, Victoria, Australia
| |
Collapse
|
|
4
|
Talapko J, Meštrović T, Škrlec I. Growing importance of urogenital candidiasis in individuals with diabetes: A narrative review. World J Diabetes 2022; 13:809-821. [PMID: 36311997 PMCID: PMC9606786 DOI: 10.4239/wjd.v13.i10.809] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2022] [Revised: 08/06/2022] [Accepted: 09/07/2022] [Indexed: 02/05/2023] Open
Abstract
Both diabetes and fungal infections contribute significantly to the global disease burden, with increasing trends seen in most developed and developing countries during recent decades. This is reflected in urogenital infections caused by Candida species that are becoming ever more pervasive in diabetic patients, particularly those that present with unsatisfactory glycemic control. In addition, a relatively new group of anti-hyperglycemic drugs, known as sodium glucose cotransporter 2 inhibitors, has been linked with an increased risk for colonization of the urogenital region with Candida spp., which can subsequently lead to an infectious process. In this review paper, we have highlighted notable virulence factors of Candida species (with an emphasis on Candida albicans) and shown how the interplay of many pathophysiological factors can give rise to vulvovaginal candidiasis, potentially complicated with recurrences and dire pregnancy outcomes. We have also addressed an increased risk of candiduria and urinary tract infections caused by species of Candida in females and males with diabetes, further highlighting possible complications such as emphysematous cystitis as well as the risk for the development of balanitis and balanoposthitis in (primarily uncircumcised) males. With a steadily increasing global burden of diabetes, urogenital mycotic infections will undoubtedly become more prevalent in the future; hence, there is a need for an evidence-based approach from both clinical and public health perspectives.
Collapse
Affiliation(s)
- Jasminka Talapko
- Laboratory for Microbiology, Faculty of Dental Medicine and Health, Josip Juraj Strossmayer University of Osijek, Osijek 31000, Croatia
| | - Tomislav Meštrović
- University North, University Centre Varaždin, Varaždin 42000, Croatia
- Institute for Health Metrics and Evaluation, Department for Health Metrics Sciences, University of Washington School of Medicine, Seattle, Washington 98195, United States
| | - Ivana Škrlec
- Department of Biophysics, Biology, and Chemistry, Faculty of Dental Medicine and Health, J. J. Strossmayer University of Osijek, Osijek 31000, Croatia
| |
Collapse
|
|
5
|
Indications that the Antimycotic Drug Amphotericin B Enhances the Impact of Platelets on Aspergillus. Antimicrob Agents Chemother 2022; 66:e0068122. [PMID: 36190233 PMCID: PMC9578436 DOI: 10.1128/aac.00681-22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Platelets are currently thought to harbor antimicrobial functions and might therefore play a crucial role in infections, e.g., those caused by Aspergillus or mucormycetes. The incidence of invasive fungal infections is increasing, particularly during the coronavirus disease 2019 (COVID-19) pandemic, and such infections continue to be life-threatening in immunocompromised patients. For this reason, the interaction of antimycotics with platelets is a key issue to evaluate modern therapeutic regimens. Amphotericin B (AmB) is widely used for the therapy of invasive fungal infections either as deoxycholate (AmB-D) or as a liposomal formulation (L-AmB). We showed that AmB strongly activates platelets within a few minutes. AmB concentrations commonly measured in the blood of patients were sufficient to stimulate platelets, indicating that this effect is highly relevant in vivo. The stimulating effect was corroborated by a broad spectrum of platelet activation parameters, including degranulation, aggregation, budding of microparticles, morphological changes, and enhanced adherence to fungal hyphae. Comparison between the deoxycholate and the liposomal formulation excluded the possibility that the liposomal part of L-Amb is responsible for these effects, as no difference was visible. The induction of platelet activation and alteration by L-AmB resulted in the activation of other parts of innate immunity, such as stimulation of the complement cascade and interaction with granulocytes. These mechanisms might substantially fuel the antifungal immune reaction in invasive mycoses. On the other hand, thrombosis and excessive inflammatory processes might occur via these mechanisms. Furthermore, the viability of L-AmB-activated platelets was consequently decreased, a process that might contribute to thrombocytopenia in patients.
Collapse
|
|
6
|
Gamal A, Kadry A, Elshaer M, Ghannoum MA, Department of Dermatology, Case Western Reserve University, Cleveland, OH, USA, These authors have contributed equally to this work and share first authorship, Department of Dermatology, Case Western Reserve University, Cleveland, OH, USA, These authors have contributed equally to this work and share first authorship, Department of Clinical Pathology, Faculty of Medicine, Mansoura University, Mansoura, Egypt, Department of Dermatology, Case Western Reserve University, Cleveland, OH, USA, Department of Dermatology, University Hospitals Cleveland Medical Center, Cleveland, OH, USA. Novel Antifungals for the Treatment of Vulvovaginal Candidiasis: Where Are We? Infect Dis (Lond) 2022. [DOI: 10.17925/id.2022.1.1.16] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Vulvovaginal candidiasis (VVC) is a common health-related issue and the second most common cause of vaginitis. Previously, azole antifungals were the mainstay of VVC treatment. Additionally, boric acid and nystatin have been used topically for management of VVC. Despite being effective and well tolerated by most patients, the use of azoles may be limited in some cases. Currently, two new antifungal agents have received US Food and Drug Administration approval for use in the management of VVC. In this article, we briefly review treatment regimens used for the management of VVC over the past decade, the newly approved agents and their possible clinical application, and future treatment considerations.
Collapse
|