Anticandidal Immunity and Vaginitis: Novel Opportunities for Immune Intervention

Abstract

The majority of human Candida infections occur at a mucosal surface. One of these infections, vulvovaginal candidiasis (VVC), is a widespread, common disease affecting a large proportion of otherwise healthy women. Some women undergo recurrent forms of VVC (RVVC); in these cases the quality of life is devastated, the associated cost of medical visits is high, there is substantial use of unprescribed therapy, and there is a possible increase in drug resistance. However, relatively little is known about the pathogenic and immunoregulatory mechanisms underlying VVC and RVVC. While there is consensus that local rather than systemic factors play a decisive role in controlling the infection, there is no consensus about the nature of the local factors. The results obtained with animal models and human investigations have not provided an overall consistent picture; rather, they have generated divergent interpretations about the role of innate and adaptive immunity against vaginal infection. Nonetheless, recent experimental evidence has resulted in some optimism concerning the challenge of clarifying the immunological basis of susceptibility to, and protection from, vaginal candidiasis through the development of appropriate immune interventions to integrate with or even replace antifungal chemotherapy.The aim of this review is to provide a short update of the evidence mentioned above and the resulting optimism. Here, we critically consider the linkage between the virulence traits of the fungus and the host responses to these traits, two interrelated aspects which have rarely been treated together in other reviews of the topic (36, 39-41, 48, 54, 56, 57, 65, 66, 74, 94, 102). On this basis, we suggest that despite substantial belief to the contrary, novel tools derived from adaptive immunity, in particular virulence-neutralizing antibodies (Abs), may become part of the anti-Candida armamentarium to fight vaginal infection.

Secreted aspartic proteases of Candida albicans activate the NLRP3 inflammasome

“…There is overwhelming experimental, and a certain amount of clinical evidence that Saps are important factors of C. albicans virulence [5,15,[51][52][53][54]. The demonstration that proinflammatory cytokine production is induced by Saps through inflammasome activation implies a new role for these virulence factors related to their structural features.…”

“…Indeed Sap2 and Sap6 provide the second signal causing direct NLRP3 activation, as demonstrated by their capacity of inducing caspase-1-dependent IL-1β production. These data suggest that Saps can genuinely activate the inflammasome, rather than spuriously affecting inflammasome auto-activation.There is overwhelming experimental, and a certain amount of clinical evidence that Saps are important factors of C. albicans virulence [5,15,[51][52][53][54]. The demonstration that proinflammatory cytokine production is induced by Saps through inflammasome activation implies a new role for these virulence factors related to their structural features.…”

Immune Response, Detection of IgE and PGE2 during Vaginal Candidiasis in Mice

“…This treatment causes changes in the thickness and keratinization of the vaginal epithelium, providing a substrate for attachment, growth and formation of a biofilm by the fungus and optimizes the experimental infection conditions (Cassone et al, 2007). Mice were intravaginally inoculated with C. albicans (1.5×10 6 cells/20 µL in saline solution), using a blunt needle.…”

Fungal Vaccines and Immunotherapeutics

“…isolated from vaginal mucosa. This protease hydrolyzes both structural and immune-associated proteins such as complement factors and immunoglobulins (Cassone et al 2007). Rats immunized with recombinant amino-terminal region of Sap-2 attached to H1N1 virosomes showed accelerated clearance of vaginal candidiasis, and were shown to produce IgA and IgG against Sap2 in vaginal fluid (De Bernardis et al 2012).…”

“…However, designing recombinant vaccines can be quite challenging because antigens have to be chosen on the basis of immunogenicity and potential effectiveness to conserve human and economic resources needed to assess potential vaccines in clinical trials. In fact, both of the subunit vaccines mentioned above were designed based on what was known about their respective antigens, particularly the antigen's role in the pathogenesis of infection (Cassone et al 2007;Phan et al 2007). When formulating recombinant fungal vaccines, special consideration must also be given to the method chosen for its synthesis, as native glycosylation is lost in bacterial expression systems.…”