Introduction

Vulvovaginal candidiasis (VVC), an inflammatory yeast infection of the vagina and/or vulva, is caused by fungal pathogens of the genera Candida, Nakaseomyces, Pichia, and other new genera, including former Candida species such as Debaryomyces, Clavispora, Kluyveromyces, Meyerozyma, Wickerhamomyces, and Yarrowia [1].When a patient experiences at least four episodes within 12 months, with two episodes confirmed by microscopy or culture when symptomatic, the condition is classified as recurrent vulvovaginal candidiasis (RVVC) [2]. Of particular concern is the high prevalence of VVC in Africa, where it affects 33% of women, with pregnant women being six times more likely to develop the infection than nonpregnant women are [3].

Despite this significant prevalence, our understanding of how African women of reproductive age respond immunologically to Candida colonization or infection remains limited. The general immune response to Candida species is well documented, beginning with barrier functions provided by epithelial cells [4]. These cells express various pathogen recognition receptors (PRRs), including Toll-like receptors (TLRs 2, 4, and 9), cysteine-like receptors (CLRs such as dectin 1, dectin 2, DC-SIGN, mincle, and mannose binding lectin), and galectin family proteins [5,6]. These PRRs recognize specific pathogen-associated molecular patterns (PAMPs) on fungi, primarily β-1,3-glucans, chitin, and mannans, initiating immune responses that vary depending on the cell types involved [5].

The immune response cascade involves several cellular components and pathways. Monocytes, macrophages, neutrophils, and epithelial cells directly combat fungal pathogens through phagocytosis [7]. Upon encountering fungal pathogens, dendritic cells mature and promote the differentiation of naïve T cells into effector T cells [4]. The binding of PAMPs to TLRs and CLRs activates multiple downstream pathways, including the SYK-CARD9 and RAF pathways, ultimately leading to the production of protective factors, such as defensins, chemokines, cytokines, reactive oxygen species, and indoleamine 2,3-dioxygenase [7].

A significant challenge in managing vaginal Candida infections is the high prevalence of asymptomatic cases, which necessitates routine screening and early detection to prevent complications and reduce transmission [8,9]. This silent nature of infections highlights the need for biomarkers that can predict the onset, replication, or resolution of vaginal Candida infections. Furthermore, given that the epidemiology and immune responses to Candida infections vary significantly by region and race owing to genetic, environmental, and microbial factors [10,11], African populations may exhibit unique immune response patterns, whose knowledge remains very limited.

This scoping review aimed to consolidate and provide a comprehensive landscape of immune markers related to vaginal candidiasis in African women. By synthesizing the available evidence, we sought to provide insights into immune mechanisms, identify research gaps, and suggest public health and clinical implications specific to this population.

Materials and methods

Results

Search results

We found 2,599 records from the database searches. After removing duplicated articles, we screened 2,407 records, from which we reviewed 19 full-text documents and ultimately included 3 papers [12–14], as shown in Fig 1.

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Fig 1. PRISMA flow diagram showing the study selection process for a scoping review on the immunology of vulvovaginal infections in Africa.

https://doi.org/10.1371/journal.pone.0322072.g001

Summary of studies

We included three studies with 1,172 participants from four African countries: South Africa, Kenya, Zambia, and Uganda Table 1

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Table 1. Cytokines, chemokines, activated immune cells and differentially expressed genes measured in each study.

https://doi.org/10.1371/journal.pone.0322072.t001

Critical appraisal of individual sources of evidence

A summary of these assessments is provided in Table 2, showing a text summary for each of the three individual segments of Newcastle Ottawa Scale, against which each record was assessed.

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Table 2. Risk of bias assessment for each study and the three domains adopted from the Newcastle Ottawa scale.

https://doi.org/10.1371/journal.pone.0322072.t002

Immune cell response

Complex immunological patterns associated with persistent, asymptomatic Candida colonization, particularly in the presence of hyphal forms, have been shown to be characterized by distinct T-cell population dynamics in the cervicovaginal environment in Kenyan women, Fig 2. The enhanced Th17 response is accompanied by a distinctive T-cell profile in which colonized individuals present reduced activation of Th17-like CD4+ T cells (CCR6+ CCR10−, HLA-DR+) at 30.10% (IQR: 16.58–42.78) compared with that of noncolonized participants (47.25%, IQR: 23.12–52.15, p = 0.018), while simultaneously exhibiting increased frequencies of Th1/Th2-enriched CCR6− CCR10− CD4+ T cells (44.70%, IQR: 34.95–53.67 vs 36.50%, IQR: 30.75–48.00, p = 0.041). Notably, the presence of HIV target cells, represented by activated CCR5 + HLA-DR + CD4+ T cells, was lower in colonized individuals (14.10%, IQR: 8.79–21.40) than in noncolonized individuals (20.00%, IQR: 10.80–30.10, p = 0.047) [14].

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Fig 2. A concept map showing cytokines, T-cell subsets, and gene expression responses linked to Candida infection.

https://doi.org/10.1371/journal.pone.0322072.g002

Discussion

This review of the inflammatory responses to vaginal candidiasis in African women reveals an intriguing and unexpected relationship between fungal colonization and HIV susceptibility. Our findings revealed a coordinated immune response characterized by elevated levels of proinflammatory cytokines (IL-1β, IL-6, and IL-8) alongside a surprising reduction in the number of HIV target cells (CCR5+ HLA-DR+ CD4+ T cells) in colonized individuals. This observation challenges the traditional paradigm that increased inflammation necessarily correlates with increased HIV susceptibility.

The distinctive pattern of immune activation observed in African women, characterized by reduced Th17-like CD4+ T-cell activation alongside increased Th1/Th2-enriched populations, appears to be further modulated by combined oral contraceptive (COC) use. This builds upon previous work [15–17], and extends our understanding by demonstrating specific impacts of hormonal contraception on immune modulation in African populations. The observed upregulation of inflammatory cytokines among COC users aligns with studies from other geographical regions [18,19], but notably, our findings suggest a more complex immune environment than previously recognized.

Our review has significant implications for treating vulvovaginal candidiasis. The cytokine patterns we observe, specifically the increased levels of IL-1β, IL-6, and IL-8, indicate that additional therapies targeting proinflammatory pathways may be beneficial in reducing symptoms and preventing recurring infections. While the decrease in HIV target cells (CCR5+ HLA-DR+ CD4+ T cells) in individuals with Candida colonization is a promising finding, it currently serves as a potential avenue for therapeutic and preventive strategies, emphasizing the need for further evidence to support these approaches

The reduced frequency of HIV target cells in colonized individuals (14.10% vs 20.00%, p = 0.047) represents a particularly important finding that warrants further investigation. This observation suggests that while Candida colonization induces robust inflammatory responses, it may simultaneously create an environment less conducive to HIV infection through mechanisms that remain to be fully elucidated. Understanding the interaction between vaginal candida colonization/infection and the expression of HIV target cells in endemic areas, such as African approaches to HIV prevention.

Thus, large-scale longitudinal studies across diverse African populations are needed to establish whether this reduction in HIV target cells is maintained over time and correlates with actual HIV acquisition risk. There is also a need to further explore the interplay between the vaginal microbiota, Candida species, and mucosal immunity to help explain how specific Candida species colonization influences HIV target cell populations in the vaginal area. Additionally, there is a need to investigate how different COC formulations affect vaginal immune responses to Candida species and inform more tailored contraceptive recommendations.

Despite limitations in the current evidence, including the small number of studies included and variations in the study designs, our findings reveal important insights into the immunology of vaginal candidiasis. A meta-analysis would have strengthened statistical insights. However, the limited number of eligible studies (n = 3) and heterogeneity in outcome measures precluded meaningful quantitative synthesis. While the influence of specific Candida strains and their interactions with the -microbiome of the vaginal environment remain unclear, the observed relationship between colonization and reduction of HIV target cells suggests that host‒pathogen interactions in the vaginal environment are more sophisticated than previously recognized. This discovery opens new avenues for understanding HIV disease susceptibility in African populations.

Conclusion

The unexpected finding of reduced HIV target cells in Candida-colonized individuals, despite elevated inflammatory markers, reveals a complex and potentially protective host‒pathogen interaction in African women that challenges the traditional understanding of vaginal immunity. Large-scale longitudinal studies across diverse African populations are urgently needed to further define the interactive mechanisms between Candida species and HIV target cells in the vaginal environment. These studies could revolutionize our approach to improving women’s health in HIV-endemic regions by informing the development of interventions that maintain beneficial immune responses while managing candidiasis.

Supporting information

Acknowledgments

We acknowledge the management of Sebbi Hospital and the staff of Sebbi Hospital Laboratory Department for granting sufficient time for the reviewers to undertake this literature review process. We also acknowledge the use of the Shiny app to generate the PRISMA checklist.