Candida vaginitis: when opportunism knocks, the host responds.

Candida albicans, an opportunistic polymorphic fungus and resident of the normal vaginal microbiota, is the leading causative agent of vulvovaginal candidiasis (VVC) and presents major quality of life issues for women worldwide [1]. Candida vaginitis is characterized by itching, burning, pain, and redness of the vulva and vaginal mucosa and often accompanied by vaginal discharge. Predisposing factors for primary VVC include high-estrogen oral contraceptive use, hormone replacement therapy, antibiotic usage, and underlying diabetes mellitus. It is estimated that 75% of all women of childbearing age will be afflicted by VVC at least once in their lifetime [2]. Of these, approximately 5–8% (approximately 150 million worldwide) suffer from recurrent VVC (RVVC), resulting in idiopathic chronic episodes of vaginal irritation that require antifungal maintenance therapy (e.g., azoles) to partially control symptoms [1]. Although these treatments are typically effective at reducing organism burden and symptoms, the static function of azole activity and fungal recalcitrance to clearance are key factors resulting in recurrence [3]. It is proposed that RVVC and VVC both involve similar immunopathologies but that the triggers occur with greater sensitivity in individuals with RVVC. Continuously rising vaginitis-related healthcare costs are estimated at $1.8 billion annually in the United States alone [4]. These unsustainable costs further necessitate a comprehensive understanding of vaginitis and the host and fungal factors that contribute to its immunopathology. The Role of Host Immunity in Candida Vaginitis: Historical and Contemporary Perspectives Susceptibility to oral, chronic mucocutaneous, and gastrointestinal candidiasis has been clearly linked to deficiencies in cell-mediated immunity (CMI) [5]. Therefore, susceptibility to Candida vaginitis was also long believed to result from defects in the adaptive immune response. However, numerous clinical studies examining women with RVVC and the use of an experimental mouse model to evaluate roles for CMI or humoral immunity (HI) revealed no appreciable protection provided by local or systemic adaptive immune mechanisms [6], [7], [8]. In support of these findings, relatively high production of immunoregulatory factors (e.g., TGF-β, T-regs, and Υ/δ T-cells) in the vagina may partly explain the lack of functional local CMI [9], [10]. Despite a lack of supportive evidence for a role of adaptive immunity in vaginitis, the newly characterized Th17 axis of CMI, which links innate and adaptive immune responses, has been shown to be critical for local protection against oropharyngeal candidiasis (OPC) [11]. Accordingly, animal models were used to determine its potential role in mucosal immunity during vaginitis. However, discrepant findings amongst mouse models have led to contradictory conclusions: one study using a less stringent pharmacologic approach to Th17 blockade demonstrated a modest role for Th17 involvement [12], while a more rigorous approach using Th17 axis-knockout mice showed no such function [12], [13]. Thus, the role of Th17 responses during vaginitis remains unresolved and lacks any supportive clinical evidence. As for mucosal HI, some animal models have demonstrated modest antibody-mediated protection against vaginitis [14]. It is conceivable that protective human antibodies do exist but occur naturally at concentrations in vaginal secretions too low to sufficiently mediate protection. While exhaustive efforts have found no major role for adaptive immunity in susceptibility to vaginitis, recent studies have identified the importance of innate immunity in regulating vaginitis symptomatology. A paramount study using women volunteers challenged with live C. albicans determined that vaginitis symptoms were associated with polymorphonuclear leukocyte (PMN) recruitment into the vagina and that organism burden alone was not predictive of disease [15]. Moreover, depletion of PMNs in mice did not result in increased fungal load but did decrease histological evidence of vaginal inflammation [16], [17]. Most recently, a family of calcium-binding proteins termed S100A8 and S100A9 “alarmins” have been implicated in the innate vaginal epithelial cell response to C. albicans (see Figure 1) [18]. Because these proteins have vigorous PMN chemotactic activity, it was hypothesized that epithelial expression of S100s may play a key role in controlling PMN migration into the vaginal lumen. However, while this was confirmed, studies using mice lacking expression of S100A8/9 proteins determined that these factors were sufficient but not necessary for driving the PMN response [19]. Collectively, these exciting new studies highlight the immunopathological response as a crucial element of vaginitis pathogenesis. Future clinical studies, however, are required to confirm the presence and function of alarmins during human infection. Figure 1 Working model of the immunopathogenesis of C. albicans vaginitis. As alluded to above, resultant findings from animal models must be translatable to the human host. One important point to consider is that laboratory rodents, unlike humans, do not naturally harbor C. albicans as commensal organisms. Although the estrogen-dependent mouse model of vaginitis closely mimics clinical infection, observed antifungal immune responses are considered primary and may be exaggerated as compared to human infection, in which repeated exposure, immunotolerance, or higher signaling thresholds to Candida may be encountered. Despite this shortcoming, the mouse model of vaginitis has been an indispensible tool for dissecting the immunological mechanisms associated with this highly complex disease.