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

Infect Immun. 2018 Feb 20;86(3):e00684-17. doi: 10.1128/IAI.00684-17. Print 2018 Mar.

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.

Publication types

  • Review

MeSH terms

  • Animals
  • Candida albicans / physiology*
  • Candidiasis, Vulvovaginal / immunology*
  • Candidiasis, Vulvovaginal / microbiology
  • Candidiasis, Vulvovaginal / pathology
  • Female
  • Humans
  • Neutrophil Infiltration
  • Neutrophils / immunology*
  • Vagina / immunology
  • Vagina / microbiology
  • Vagina / pathology