It Takes Two to Tango: How a Dysregulation of the Innate Immunity, Coupled With Candida Virulence, Triggers VVC Onset

Abstract

Vulvovaginal candidiasis (VVC) is a symptomatic inflammation of the vagina mainly caused by C. albicans. Other species, such as C. parapsilosis, C. glabrata, C. tropicalis, and C. krusei, are mainly associated to the recurrent form of the disease (RVVC), although with a lower frequency. In its yeast form, C. albicans is tolerated by the vaginal epithelium, but switching to the invasive hyphal form, co-regulated with the expression of genes encoding virulence factors such as secreted aspartyl proteases (Sap) and candidalysin, allows for tissue damage. Vaginal epithelial cells play an important role by impairing C. albicans tissue invasion through several mechanisms such as epithelial shedding, secretion of mucin and strong interepithelial cell connections. However, morphotype switching coupled to increasing of the fungal burden can overcome the tolerance threshold and trigger an intense inflammatory response. Pathological inflammation is believed to be facilitated by an altered vaginal microbiome, i.e., Lactobacillus dysbiosis. Notwithstanding the damage caused by the fungus itself, the host response to the fungus plays an important role in the onset of VVC, exacerbating fungal-mediated damage. This response can be triggered by host PRR-fungal PAMP interaction and other more complex mechanisms (i.e., Sap-mediated NLRP3 activation and candidalysin), ultimately leading to strong neutrophil recruitment. However, recruited neutrophils appear to be ineffective at reducing fungal burden and invasion; therefore, they seem to contribute more to the symptoms associated with vaginitis than to protection against the disease. Recently, two aspects of the vulvovaginal environment have been found to associate with VVC and induce neutrophil anergy in vitro: perinuclear anti-neutrophil cytoplasmic antibodies (pANCA) and heparan sulfate. Interestingly, CAGTA antibodies have also been found with higher frequency in VVC as compared to asymptomatic colonized women. This review highlights and discusses recent advances on understanding the VVC pathogenesis mechanisms as well as the role of host defenses during the disease.

Treating (Recurrent) Vulvovaginal Candidiasis with Medical-Grade Honey—Concepts and Practical Considerations

“…The pathogenesis of VVC is a gradual process that goes through several stages, from adherence to the vaginal epithelium, recognition (caused by a burden threshold of hyphae), becoming invasive, the possibility of biofilm formation, and dispersion of planktonic cells that reinitiates the complete process (see Figure 1). more complex mechanisms (i.e., secreted aspartyl proteases (Sap)-mediated NLRP3 activation and the cytolytic peptide toxin candidalysin) [17,18]. The activation of the innate immune system by a series of proinflammatory cytokines and chemokines leads to the recruitment of neutrophils to the vaginal mucosa, subsequently exacerbating symptomatic disease [17][18][19].…”

“…There seems to be a local mucosal overreaction caused by an exaggerated inflammatory response responsible for vulvovaginal symptoms [ 1 , 4 ]. This response can be triggered by host pattern recognition receptors (PRP) interacting with fungal pathogen-associated molecular patterns (PAMPs) and other more complex mechanisms (i.e., secreted aspartyl proteases (Sap)-mediated NLRP3 activation and the cytolytic peptide toxin candidalysin) [ 17 , 18 ]. The activation of the innate immune system by a series of proinflammatory cytokines and chemokines leads to the recruitment of neutrophils to the vaginal mucosa, subsequently exacerbating symptomatic disease [ 17 , 18 , 19 ].…”

“…This response can be triggered by host pattern recognition receptors (PRP) interacting with fungal pathogen-associated molecular patterns (PAMPs) and other more complex mechanisms (i.e., secreted aspartyl proteases (Sap)-mediated NLRP3 activation and the cytolytic peptide toxin candidalysin) [ 17 , 18 ]. The activation of the innate immune system by a series of proinflammatory cytokines and chemokines leads to the recruitment of neutrophils to the vaginal mucosa, subsequently exacerbating symptomatic disease [ 17 , 18 , 19 ]. Moreover, Candida species also can exert tissue damage by direct invasion of its hyphal filaments or secretion of virulence effectors [ 19 ].…”

“…Candida species have a dual lifestyle as both a vaginal commensal and an opportunistic pathogen [ 20 ]. The switch between yeast and hyphal growth is critical for virulence, affecting numerous properties including phenotypic and biochemical properties [ 18 , 21 ]. Virulence traits are created by microorganisms and may subsequently lead to tissue damage, making them more pathogenic [ 22 ].…”

“…Virulence traits are created by microorganisms and may subsequently lead to tissue damage, making them more pathogenic [ 22 ]. Virulence traits include the ability to make a morphological switch from yeast to hyphae, modulating the expression of adhesins to help the Candida adhere to epithelial cells, the expression of invasins, the formation of biofilms, the secretion of hydrolytic enzymes such as Sap and candidalysin, and the ability to escape from phagocytosis by neutrophils and macrophages [ 17 , 18 , 23 , 24 , 25 ].…”