Novel Mechanism behind the Immunopathogenesis of Vulvovaginal Candidiasis: "Neutrophil Anergy"

Abstract

For over 3 decades, investigators have studied the pathogenesis of vulvovaginal candidiasis (VVC) and recurrent VVC (RVVC) through clinical studies and animal models. While there was considerable consensus that susceptibility was not associated with any apparent deficiencies in adaptive immunity, protective immune mechanisms and the role of innate immunity remained elusive. It was not until an innovative live-challenge design was conducted in women that a fuller understanding of the natural history of infection/disease was achieved. These studies revealed that symptomatic infection is associated with recruitment of polymorphonuclear neutrophils (PMNs) into the vaginal lumen. Subsequent studies in the established mouse model demonstrated that infiltrating PMNs were incapable of reducing the fungal burden, which supported the hypothesis that VVC/RVVC was an immunopathology, whereby Candida and the host response drive symptomatic disease. Further studies in mice revealed the requirement for C. albicans hyphae and identified pattern recognition receptors (PRRs) and proinflammatory mediators responsible for the PMN response, all of which are critical pieces of the immunopathogenesis. However, a mechanism explaining PMN dysfunction at the vaginal mucosa remained an enigma. Ultimately, by employing mouse strains resistant or susceptible to chronic VVC, it was determined that heparan sulfate (HS) in the vaginal environment of susceptible mice serves as a competitive ligand for Mac-1 on PMNs, which effectively renders the PMNs incapable of binding to Candida to initiate killing. Hence, the outcome of symptomatic VVC/RVVC is postulated to be dependent on a PMN-mediated immunopathogenic response involving HS that effectively places the neutrophils in a state of functional anergy.

Keywords: Candida albicans; inflammation; innate immunity; neutrophils; vaginitis.

FIG 1

Proposed host-pathogen interactions leading to the immunopathogenic response in mice susceptible to chronic vulvovaginal candidiasis (CVVC). (A) Initiation of the PMN-mediated immunopathological response. Following inoculation with C. albicans, the hypha-inducing environment (i.e., elevated pH, increased estrogen) promotes epithelial signaling by Candidalysin and, together with fungal-epithelial cell recognition via the pattern recognition receptors (PRRs) TLR4 and SIGNR1, results in epithelial cell activation. Downstream signaling events lead to production of key inflammatory mediators, including S100A8 alarmin and IL-1β, via the NLRP3 inflammasome. Due to their potent chemotactic properties, the increased presence of the inflammatory mediators leads to robust recruitment of PMNs to the vaginal cavity, resulting in an acute inflammatory state. (B) Symptomatic/immunopathological state of the vaginal epithelium in a CVVC-susceptible environment. Recruited activated PMNs lose their antifungal killing capacity once reaching the vaginal lumen and fail to clear C. albicans. The ensuing fungal overgrowth continues to elicit the initial triggers by the vaginal epithelium, while the production of the inflammatory mediators is amplified (feedback loop) from the activated PMNs. Insufficient regulation of the inflammatory response enhances the immunopathogenic processes and, together with tissue damage by C. albicans, results in the symptomatic environment.

FIG 2

Schematic model representing normal PMN function in CVVC-resistant mice and the mechanism for “neutrophil anergy” in CVVC-susceptible mice. (A) Effective fungal recognition and clearance by PMNs in a CVVC-resistant mouse strain. Production of heparan sulfate (HS) by the vaginal epithelium is minimal in estrogen-hyporesponsive CD-1 mice. Following intravaginal inoculation with C. albicans, PMNs are recruited to the vaginal lumen and further activated via Mac-1 receptor binding to C. albicans surface protein Pra1. The interaction of Mac-1 with Pra1 is sufficient to mediate fungal killing by PMNs, leading to rapid fungal clearance and timely resolution of acute inflammation. (B) Lack of fungal clearance by PMNs in a CVVC-susceptible mouse strain. Production of HS by the vaginal epithelium is elevated in mice with normal estrogen responsiveness. Increased levels of HS in the vaginal lumen block recognition of C. albicans Pra1 by PMNs by acting as a competitive ligand for Mac-1. The failure of activated PMNs to adequately recognize C. albicans results in the inhibition of PMN killing (PMN anergy) despite a sustained acute inflammatory response, placing the vaginal mucosa in a chronic immunopathological state.