Cytokines in the host response to Candida vaginitis: Identifying a role for non-classical immune mediators, S100 alarmins

Abstract

Vulvovaginal candidiasis (VVC), caused by Candida albicans, affects a significant number of women during their reproductive years. More than two decades of research have been focused on the mechanisms associated with susceptibility or resistance to symptomatic infection. Adaptive immunity by Th1-type CD4(+) T cells and downstream cytokine responses are considered the predominant host defense mechanisms against mucosal Candida infections. However, numerous clinical and animal studies have indicated no or limited protective role of cells and cytokines of the Th1 or Th2 lineage against vaginal infection. The role for Th17 is only now begun to be investigated in-depth for VVC with results already showing significant controversy. On the other hand, a clinical live-challenge study and an established animal model have shown that a symptomatic condition is intimately associated with the vaginal infiltration of polymorphonuclear leukocytes (PMNs) but with no effect on vaginal fungal burden. Subsequent studies identified S100A8 and S100A9 alarmins as key chemotactic mediators of the acute PMN response. These chemotactic danger signals appear to be secreted by vaginal epithelial cells upon interaction and early adherence of Candida. Thus, instead of a putative immunodeficiency against Candida involving classical immune cells and cytokines of the adaptive response, the pathological inflammation in VVC is now considered a consequence of a non-productive innate response initiated by non-classical immune mediators.

Figure 1

Presence of PMNs in vaginal lavage fluid following inoculation with C. albicans. (A) Vaginal smears collected on day 7 post-inoculation from women who acquired a symptomatic infection (symptomatic condition), became asymptomatically colonized (asymptomatic condition) or uninoculated women. (B) Vaginal smears collected on day 7 post-inoculation from estrogen-treated inoculated mice with high PMNs (symptomatic condition), low PMNs (asymptomatic condition) or uninoculated mice. Smear samples were preserved and stained using the Papanicolaou technique. Images are shown at X400 magnification. Inserts show a high-magnified view of PMNs at 120% of X1,000 magnification. Partially reproduced with permission from ASM Press.

Figure 2

Schematic diagrams representing the mechanism for the effects of vaginal S100 alarmins on PMN migration during VVC. (A) Epithelial cell sensitivity – organism threshold hypothesis. In women with no history of VVC (left panel), their vaginal epithelial cells are insensitive to Candida. These women remain asymptomatic as even in the presence of high numbers for Candida (threshold number to initiate pathological response rarely breached). In women with RVVC (right panel), vaginal epithelial cells are extremely sensitive to Candida. These women are susceptible to symptomatic infection following exposure to even small numbers of Candida (low organism threshold). The thresholds represent an arbitrary organism number of the upper limit for vaginal fungal burden that would initiate symptomatic infection. (B) Consequences of epithelial cell sensitivity. Under asymptomatic condition (left panel), vaginal epithelial cells are insensitive to Candida and remain unstimulated following interaction with Candida. In turn, PMN migration does not occur in the absence of S100 alarmin production. Strong cell-surface Annexin A1-dependent (proposed based on oral epithelial cells) antifungal activity provides non-inflammatory means to maintain Candida at the commensal state. Under symptomatic conditions (right panel), vaginal epithelial cells are extremely sensitive to Candida and exert weak antifungal activity through Annexin A1. Epithelial cells become activated upon recognition of Candida via unidentified PRRs. S100 alarmins are secreted as danger signals toward which vaginal PMNs migrate through vaginal epithelium. Once in the vaginal epithelium, recruited PMNs also produce S100 alarmins as part of positive feedback mechanism to further amplify the PMN response. (C) S100 alarmin response in immunopathogenesis. PMN infiltration remains minimal in the absence of S100 alarmin production by vaginal epithelial cells, therefore, no symptom occurs (left panel). In contrast, high concentrations of S100 alarmins in vaginal epithelium trigger PMN migration to the vaginal cavity, resulting in pathological inflammation associated with the symptoms of infection. The inflammatory process enhances Candida growth and hyphal formation (right panel).