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Should we absolutely reject the hypothesis that epithelium-based Candida biofilms contribute to the pathogenesis of human vulvovaginal candidiasis?

      To the Editors:
      We read the article by Swidsinski et al
      • Swidsinski A.
      • Guschin A.
      • Tang Q.
      • et al.
      Vulvovaginal candidiasis: histologic lesions are primarily polymicrobial and invasive and do not contain biofilms.
      with great interest. The authors used fluorescent in situ hybridization of human vaginal tissue biopsies to demonstrate the absence of Candida biofilms in patients with vulvovaginal candidiasis (VVC). This is a very important finding because it might reset the treatment target for recurrent VVC (RVVC) from biotic biofilms to invasive fungi.
      However; from the microbiologic aspect, it is reasonable to assume the involvement of Candida biofilms in VVC and their resistance to antifungals. Although most clinical isolates from patients with RVVC/VVC remain sensitive to conventional antifungal agents, the ineffectiveness of these drugs in curing RVVC is reported frequently. This suggests that microbial strategies other than intrinsic resistance might be involved. Such possible strategies include biofilm formation and production of persister cells (a small population of “transiently resistant” cells). Supporting this suggestion is the observation that the recurrence pattern of RVVC coincides with the model of relapsing biofilm infections proposed by Lewis
      • Lewis K.
      Persister cells.
      (2010), in which persister cell are major culprits.
      Harriot et al
      • Harriott M.M.
      • Lilly E.A.
      • Rodriguez T.E.
      • Fidel Jr., P.L.
      • Noverr M.C.
      Candida albicans forms biofilms on the vaginal mucosa.
      (2010) successfully demonstrated vaginal epithelium-based Candida biofilms using a mouse VVC model and raised the hypothesis that formation of such biofilms may be an initiating event in VVC. Using the same model, Zhang et al
      • Zhang J.E.
      • Luo D.
      • Chen R.Y.
      • Yang Y.P.
      • Zhou Y.
      • Fan Y.M.
      Feasibility of histological scoring and colony count for evaluating infective severity in mouse vaginal candidiasis.
      (2013) found a dynamic change of Candida growth on vaginal epithelia along with VVC progression. Candida pseudohyphae and yeast cells were found on mouse vaginal epithelia 3 days after the infection; these adherent biofilms were replaced gradually by the endocytosed hyphae, which is a unique growth mode also reported by Swidsinski et al.
      • Swidsinski A.
      • Guschin A.
      • Tang Q.
      • et al.
      Vulvovaginal candidiasis: histologic lesions are primarily polymicrobial and invasive and do not contain biofilms.
      The possibility of the presence of such transient biofilms in patients whose infections have progressed to a later stage should not be excluded. Furthermore, although the endocytosed yeast/hyphal cells in vaginal epithelia do not present any structural characteristics of typical multilayer biofilms, such as the presence of self-producing polymeric matrix or 3-dimensional mushroom structures, they might resemble monolayer biofilms and share some important traits that drive the recurrence of infections, which includes harboring antifungal-tolerant persister cells. We have found that dense growth of monolayer biofilms in a confined space stimulated persister cell production and led to antimicrobial tolerance in vitro.
      • Qu Y.
      • Daley A.J.
      • Istivan T.S.
      • Rouch D.A.
      • Deighton M.A.
      Densely adherent growth mode, rather than extracellular polymer substance matrix build-up ability, contributes to high resistance of Staphylococcus epidermidis biofilms to antibiotics.
      The further clarification of the possible dynamic change of Candida growth in the human vagina VVC and whether the endocytosed hyphal cell growth mode promotes persister cell production needs collaborative efforts from experimental microbiologists and clinical investigators.

      References

        • Swidsinski A.
        • Guschin A.
        • Tang Q.
        • et al.
        Vulvovaginal candidiasis: histologic lesions are primarily polymicrobial and invasive and do not contain biofilms.
        Am J Obstet Gynecol. 2019; 220: 91.e1-91.e8
        • Lewis K.
        Persister cells.
        Ann Rev Microbiol. 2010; 64: 357-372
        • Harriott M.M.
        • Lilly E.A.
        • Rodriguez T.E.
        • Fidel Jr., P.L.
        • Noverr M.C.
        Candida albicans forms biofilms on the vaginal mucosa.
        Microbiology. 2010; 156: 3635-3644
        • Zhang J.E.
        • Luo D.
        • Chen R.Y.
        • Yang Y.P.
        • Zhou Y.
        • Fan Y.M.
        Feasibility of histological scoring and colony count for evaluating infective severity in mouse vaginal candidiasis.
        Exper Anim. 2013; 62: 205-210
        • Qu Y.
        • Daley A.J.
        • Istivan T.S.
        • Rouch D.A.
        • Deighton M.A.
        Densely adherent growth mode, rather than extracellular polymer substance matrix build-up ability, contributes to high resistance of Staphylococcus epidermidis biofilms to antibiotics.
        J Antimicrob Chemother. 2010; 65: 1405-1411

      Linked Article

      • Vulvovaginal candidiasis: histologic lesions are primarily polymicrobial and invasive and do not contain biofilms
        American Journal of Obstetrics & GynecologyVol. 220Issue 1
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          The recent demonstration of a vaginal biofilm in bacterial vaginosis and its postulated importance in the pathogenesis of recurrent bacterial vaginosis, including relative resistance to therapy, has led to the hypothesis that biofilms are crucial for the development of vulvovaginal candidiasis. The histopathology and microbial architecture of vulvovaginal candidiasis have not been previously defined; neither has Candida, containing biofilm been reported in situ. The present study aimed at clarifying the histopathology of vulvovaginal candidiasis including the presence or absence of vaginal biofilm.
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        American Journal of Obstetrics & GynecologyVol. 221Issue 2
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          We appreciate the thoughtful comments of Noverr and Fidel as to the findings in our recent publication evaluating the presence of Candida-associated biofilm in women with acute vulvovaginal candidiasis (VVC).1 The study produced 2 conclusions: (1) the extensive and previously unreported human vaginal mucosal invasion and infiltration by Candida microorganisms as well as the clinical consequences of tissue invasion; and (2) failure to document using a well-described and widely used technique of fluorescent in situ hybridization with ribosomal gene-based probes, the presence of microscopic biofilm, containing Candida species microorganisms.
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        American Journal of Obstetrics & GynecologyVol. 221Issue 4
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          Phantom limb sensations are obviously very strong in the Candida-biofilm research community. It is striking that this and previous letters to the editor with regard to our publication,1 cite Harriott et al2 as work that definitively demonstrated the vaginal candida biofilm in rodents. That is not true. We likewise cite the same author in our article and state that “The only publication claiming Candida albicans forms biofilms on the vaginal mucosa exclusively includes pictures of smears from vagina without vaginal epithelium.”
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