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Impact of interkingdom microbial interactions in the vaginal tract

Citation: Cohen S, Ost KS, Doran KS (2024) Impact of interkingdom microbial interactions in the vaginal tract. PLoS Pathog 20(3): e1012018. https://doi.org/10.1371/journal.ppat.1012018

Editor: Jorn Coers, Duke University School of Medicine, UNITED STATES

Published: March 8, 2024

Copyright: © 2024 Cohen et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Funding: This work in the Doran lab is supported by NIH grant R01AI153332 to K.S.D. Work in the Ost lab is supported by NIH grants DP2AI177827, the Cifar Azrieli Global Scholars program, and a Crohn’s and Colitis Foundation Career Development Award (884308). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: The authors have declared that no competing interests exist.

Introduction to the important fungal and bacterial players

Studies from recent years have identified a diverse population of both bacteria and fungi in the human vagina and several community signatures have emerged that are associated with susceptibility to infectious disease. A healthy vaginal bacterial microbiome is most frequently dominated by Lactobacillus species [1], yet a combination of other genera are isolated in vaginal swabs in both healthy and diseased states. The vaginal fungal mycobiome is dominated by Ascomycota, of which Candida species are the most abundant. Approximately 20% to 30% of healthy human vaginal samples contain detectable Candida at a single time point, with nearly all of those being C. albicans, and 70% of the population is expected to be vaginally colonized with Candida longitudinally [2].

Despite its prevalence in the healthy vaginal mycobiome, C. albicans is the most common causative agent of vulvovaginal candidiasis (VVC), a cause of significant morbidity in the human population. The next most common species implicated in VVC is C. glabrata, while other species including C. lusitaniae, C. tropicalis, C. parapsilosis, and C. krusei are also known to contribute to vaginal infections [3–5]. Non-albicans Candida species are typically more resistant to antifungal drugs than C. albicans [6], complicating therapeutic options and increasing treatment timelines. A disease state is often distinguished by an exaggerated inflammatory response at the vaginal mucosa [3] that leads to vulvar pruritis and erythema [7]. Polymorphic Candida species can initiate the process of filamentation, morphogenesis from single-celled yeast to multicellular hyphae, which is typically accompanied by increased tissue damage and inflammation [8]. Microbial dysbiosis has long been associated with VVC due to the observation that antibiotic usage dramatically increases the risk of onset. This notion has been challenged by several population studies [9,10]; however, other studies have found a close association between Candida and specific bacteria as well as distinct Lactobacillus species that were associated with decreased observation of fungi in samples or symptomatic VVC [11–15]. Taken together, the evidence suggests that specific bacterial species can have complex impacts on fungal burden and symptomatic infection. Shifts in the vaginal microbiome are also associated with other genital tract infections [13,16] including bacterial vaginosis (BV) and aerobic vaginitis (AV), which are characterized by the displacement of Lactobacillus species by other bacteria such as Gardnerella vaginalis, Streptococcus agalactiae, Staphylococcus aureus, Escherichia coli, and Enterococcus faecalis [17]. Both BV and AV are polymicrobial in nature and are associated with concurrent Candida carriage in many cases [18,19]. Mixed vaginitis, which can include BV or AV together with VVC, is particularly difficult to treat, and during late stages of pregnancy can lead to severe adverse maternal and neonatal outcomes [17,20]. Because it is the most abundant fungal genus in the vagina, this review will focus on the interactions between Candida species and the healthy and pathogenic bacteria found in the vaginal environment. These interactions play a significant role in maintaining homeostasis as well as impacting disease pathogenesis in the genital tract (Fig 1).

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Fig 1. Bacterial interactions with fungi in the vaginal tract take on many forms.

Metabolic products, surface proteins, and isolated bacterial components can all impact fungal growth and physiology at the epithelial surface. The vaginal microbiome similarly affects host epithelial biology and immune responses to commensal and pathogenic organisms. In combination, the activities of bacteria and fungi in this environment contribute to the pathology of vaginal infections. Figure created using BioRender.com.

https://doi.org/10.1371/journal.ppat.1012018.g001

How does the native vaginal microbiome limit fungal infection?

Although the composition of the vaginal microbiome varies between individuals, many are dominated by one species of Lactobacillus [21]. This genus is largely considered protective against VVC as lactobacilli secrete numerous factors that can inhibit Candida pathogenicity including lactic acid, short and medium chain fatty acids, biosurfactants, bacteriocins, chitinases, and hydrogen peroxide [22]. Lactic acid and fatty acids contribute to the acidic pH typical of the human vaginal tract. Low pH promotes the yeast morphotype [23] of polymorphic Candida species which is the less pathogenic morphotype compared to hyphae due to its limited adhesive and invasive capabilities. While this could play a significant role in the vagina, its relevance in humans remains to be determined. Importantly, pH measurements reflect the bulk environment of the vaginal lumen. In its local environment, C. albicans can modify the pH [24], metabolize lactic acid [25], and respond to extracellular lactate by remodeling its cell wall to shield immune stimulatory glycans [26]. Lactobacillus-derived biosurfactants [27] have been reported to interrupt fungal adherence to epithelial cells, limiting opportunities for invasion and tissue damage. Bacteriocins and chitinases produced by lactobacilli directly attack Candida species [28], hydrolyzing the fungal cell wall and forming pores. Broadly, the secretome has been shown to reduce Candida adherence and biofilm-associated gene expression [29–31]. Beyond secreted factors, Lactobacillus species also associate closely with vaginal epithelial cells which reduces Candida adherence by way of competitive binding.

The relevance of hydrogen peroxide production on restricting the growth of fungal pathogens in vivo is debated in the literature [32] due to the requirement for oxygen in its biosynthesis and the high concentrations necessary to prevent hyphal morphogenesis. Physiological concentrations of hydrogen peroxide in the vagina are 5 to 25 μm, and C. albicans growth restriction begins in the mM range; however, local concentrations likely exceed the measured quantities and may be sufficient for inhibition. Furthermore, L. crispatus, which produces peroxide, is most associated with protection against C. albicans vaginal infection while L. iners, which does not produce peroxide, is regarded as least protective and often co-occurs with pathogenic microbes. An L. iners-dominated vaginal microbiome is thus associated with a higher risk of VVC [13,14,33].

Bifidobacterium species are also documented commensals of the vaginal microbiome, yet their interactions with fungal species in the genital tract are less well studied. Human gastrointestinal Bifidobacterium isolates have been shown to inhibit C. albicans growth [34]. Other studies have demonstrated that they can attenuate the pathogenesis of C. albicans and Clostridioides difficile gut coinfections [35]. These results may indicate a protective role for Bifidobacterium in the vagina, yet VVC diagnosis, particularly C. glabrata VVC, has been associated with an increase in relative Bifidobacterium abundance [36]. Thus, further studies are required to dissect the role of bifidobacteria in Candida pathogenesis.

How do pathogenic bacteria interact with Candida during infection?

Interactions between C. albicans and the pathogenic bacteria that it encounters have been described for several host environments including the oral cavity, skin, lungs, gastrointestinal tract, and blood. In many cases, fungal–bacterial interactions promote disease severity and increase antimicrobial resistance. Similarly to these other niches, Candida species often co-occur with bacterial opportunistic pathogens in the genital tract.

The bacteria that C. albicans interacts with are known to modulate its adhesive abilities and biofilm formation. C. albicans encodes a repertoire of adhesive surface proteins that are critical for its adhesion to a wide range of substrates. Additionally, these adhesins mediate physical interactions with other microbes including S. aureus, a causative agent of AV that has been co-isolated with C. albicans in vaginal swabs. S. aureus has been described in association with C. albicans in numerous studies [20,37,38]. They are known to form robust polymicrobial biofilms together, a physical interaction mediated in part by the agglutinin-like sequence (Als) family of adhesins. S. aureus does not inhibit hyphal morphogenesis in co-culture with C. albicans; however, studies have shown that its purified alpha-hemolysin can inhibit filamentation and is protective in an in vivo model of VVC [39]. Alternatively, peptidoglycan subunits from both S. aureus and E. coli promote C. albicans filamentation [40,41]. E. coli, which has also been co-isolated with C. albicans in vaginal swabs [42], dramatically alters the structure of a C. albicans biofilm, presumably by affecting fungal factors such as filamentation that are involved in biofilm formation and maintenance. Work in vitro demonstrates that Candida and E. faecalis, a pathobiont found in the vaginal tract [43,44], communicate using secreted factors controlled by the Fsr quorum-sensing system including EntV, which reduces C. albicans adhesion and filamentation [45,46]. Quorum sensing is also well known to play a role in Candida interactions with S. aureus. C. albicans induces the accessory gene regulator (agr) system in S. aureus [47], and the fungal quorum-sensing molecule farnesol up-regulates staphylococcal efflux pumps [48]. It is unknown whether this occurs in the genital tract and what the implications are for C. albicans carriage, but this warrants further studies on the consequences of their co-occurrence in this environment.

S. agalactiae, also known as Group B Streptococcus (GBS), is a pathobiont that colonizes the vaginal tract and is associated with pregnancy complications including chorioamnionitis, preterm premature rupture of membranes, and preterm labor, as well as invasive infections in the newborn [49,50]. Many population studies show a significant association between GBS and C. albicans vaginal carriage [51–55]. C. albicans has been shown to increase GBS adherence to vaginal epithelial cells due to co-association mediated by the fungal agglutinin-like sequence protein 3 (Als3) and GBS adhesins in the antigen I/II (AgI/II) protein family [56]. The contribution of Als3 to polymicrobial interactions is further illustrated by GBS preferentially binding to hyphae, which express Als3 on their surface, compared to the yeast morphotype of C. albicans, which do not. There is also evidence that GBS impacts C. albicans pathogenesis. In vitro, GBS may inhibit C. albicans filamentation as well as increase fungal burdens in a murine model of vaginal infection [57]. A growing body of work describes the mechanisms of C. albicans interactions with other streptococci in the oral cavity [37,58,59]. This raises the question of whether C. albicans and GBS are also interacting through extracellular signals and secreted metabolites in addition to adhesin-mediated physical binding.

Population studies of the human vaginal microbiome have revealed associations between BV pathogens and fungi. Gardnerella vaginalis is positively correlated with C. lusitaniae VVC and has been imaged in direct association with invasive Candida hyphae in human biopsy samples [11]. Prevotella bivia is highly abundant in individuals with C. glabrata VVC, and Peptostreptococcus species are positively correlated with C. parapsilosis VVC. These patterns suggest that individual species of Candida may have unique bacterial interaction profiles.

What aspects of the host environment dictate interactions?

In addition to directly antagonizing C. albicans pathogenicity, Lactobacillus species may support host defenses against VVC. They have been shown to increase mucus production in the vagina as well as promote tight junction maintenance and antimicrobial peptide production [28,60]. These factors likely play a role in preventing fungal invasion into the epithelium and subsequent tissue damage. Mucosal epithelial features of the vaginal environment greatly influence C. albicans pathogenicity and can be modulated by resident microbes. C. albicans secreted proteases hydrolyze hemoglobin present in the lumen, producing antimicrobial hemocidins [61] with broad activity against L. acidophilus and E. coli. Additionally, C. albicans can initiate the release of arachidonic acid from host cells [62], which it can not only utilize as a carbon source to promote growth but also to generate oxylipins [63]. These have been shown to contribute to weakened tight junctions and an increased inflammatory response.

Mounting evidence strongly indicates that VVC symptoms are mediated by the host inflammatory response to fungal factors [3,64]. Interestingly, a vaccine that enhances an Als3-specific antibody response is protective against both recurrent VVC as well as S. aureus infection [65–67]. This suggests that a shared epitope may mediate cross-kingdom protection or that an immune response against Candida could promote S. aureus clearance indirectly. Further, this highlights that in the absence of vaccination, the inflammatory response is nonprotective against these 2 pathogens and may cause immunopathology during infection. L. crispatus could play a role in dampening the native nonprotective response against C. albicans by altering the cytokine profile [68]. Among these alterations, it has been demonstrated to induce IL-1RA and IL-2 secretion in vaginal epithelial cells and inhibit IL-6, IL-8, TNFα, RANTES, and MIP3α during in vitro infection with C. albicans. IL-1RA has a demonstrated role in protection against pathogenic inflammation during VVC [69,70], and these findings highlight an avenue for further investigation into the activity of IL-2 and other cytokines in this environment. Together, this may support a potential role for select lactobacilli in suppressing inflammatory immune responses and preventing VVC pathogenesis. L. crispatus has also been shown to increase IL-17 release by vaginal epithelial cells in response to C. albicans infection [60], yet it is unclear whether this is protective against VVC. Some studies show that a Th17 response is beneficial while others dispute this, indicating that it plays a nuanced role in this environment [71–74]. Recruited neutrophils can exacerbate VVC pathology [8,75–77], yet antimicrobial peptide production involved in the Th17 response can facilitate fungal clearance [71]. Although mechanistic studies in humans are limited, human genetic deficiencies in IL-17 and IL-22 production have been associated with a higher risk of VVC [78,79]. Interestingly, GBS attenuates the Th17 immune response to C. albicans in a murine model of VVC [57], which may contribute to increased fungal burdens in the vaginal lumen during coinfection. The role of several cytokine responses to VVC has been reviewed in depth [72,80].

Conclusion

The diverse communities of bacteria and fungi in the genital tract lend themselves to an equally diverse array of interkingdom interactions. Understanding the mechanisms by which these interactions occur and impact vaginal health is critical to developing therapeutic strategies to treat infection in this dynamic and polymicrobial environment. Significant work remains to characterize the interkingdom interactions that occur in this unique host niche.

Acknowledgments

The authors appreciate the contribution of all the researchers whose work has been reviewed here as well as those whose work may not have been discussed in detail due to space constraints.

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