Abstract Vulvovaginal candidiasis is a common mucosal infection affecting a large proportion of women with some of them affected by recurrent often intractable forms of the disease. Thus, there is an increasing interest in understanding the pathogenesis of this disease. The aim of our work was to characterize, in animal models of vaginal candidiasis, the components of the host-fungus interaction at the mucosal level. The evidence of an immune response in the vaginal compartment was very encouraging to identify the proper targets for new strategies for vaccination or immunotherapy of vaginal candidiasis. Aspartyl-proteinase (Sap2), which is an important immunodominant antigens and virulence factors of C.albicans acting in mucosal infections, was assembled with virosomes and a vaccine PEV7 was obtained. The results obtained in the mouse model and in the clinical trial conducted by Pevion on women have evidenced that the vaccine PEV7, intravaginally administered, has an encouraging therapeutic potential for the treatment of recurrent vulvovaginal candidiasis. This opens the way to a modality for anti-Candida protection at mucosal level. Candida vaginitis, virulence factors, aspartyl-proteinase, immune-response, mucosal anti-Candida vaccine Introduction The aim of this working group is to extend previous clinical and microbiological investigations and to understand host-parasite interactions in candidiasis and try to generate novel efficient therapeutic and/or immunological tools. Particularly, we will try to understand the fungal and host components involved in the pathogenesis of mucosal candidiasis and to assess the role of aspartic proteinase (Sap) in Candida virulence and pathogenicity and to investigate the mechanisms induced in the vagina during Candida infection and to identify specific Candida molecules potentially useful for vaccination or immunotherapy of vaginal candidiasis. Vaginal candidiasis is one of the most frequent infections of the female genital tract of women of reproductive age. At least 75% of women suffer once in their life from one episode of a Candida infection. In more than 85% of the cases, vulvovaginal candidiasis is primarily caused by C. albicans, followed by C. glabrata with 4–5%, and to a lesser extent, by C. tropicalis and C. parapsilosis.1–5 Predisposing factors in getting an acute form of vaginal candidiasis are well-known and include immunosuppression-diseases, endocrine diseases, antibiotic therapy or diabetes.3,4 Patients, suffering at least four episodes of Candida infection during 1 year, have a recurrent infection and are therefore recognized and classified as recurring vulvovaginal candidosis (RVVC) patients.1,4 Epidemiological investigations have suggested that the prevalence of RVVC may be higher than previously estimated and can be as high as 7–8% of women who experience a first episode. This would translate into an estimated global annual incidence ranging of 1–2% of all women.6–8 The discomfort associated with RVVC is intense; it markedly diminishes the quality of life in young women. The well-known predisposing factors seem not to play an important role in recurrent Candida infections. The causal reasons for getting multiple recurrences of a Candida infection are multivarious and still not well understood. The widespread occurrence of vaginal infections caused by Candida, and the development of resistance against available drugs require the need for new specific antifungal agents and the discovery of new drug-target.9–15 It is also suggested a genetic predisposition among individual patients; thus, gene polymorphisms are to be included as a predisposing factor which puts women at risk for VVC and RVVC.16–19 Therefore, understanding the components of the host-fungus interaction at the mucosal level can lead to a better understanding of the pathogenesis of mucosal candidiasis and result in the optimization of preventive and therapeutic antifungal strategies. Moreover, in contrast to systemic candidiasis, relatively little is known about the role of mucosal immunity in protection against Candida. C. albicans is capable of colonizing and persisting on mucosal surfaces of the oral cavity and of the gastrointestinal and genitourinary tracts of healthy humans where its presence stimulates mucosal responses. Odds has suggested that 40–50% of any given sample population temporarily or permanently carry this fungus in their gastrointestinal tract.20 The transition of C. albicans from asymptomatic colonization to symptomatic vaginitis is primarily the consequence of a defective host cellular immune response, but of some relevance can be also the virulence of C. albicans strains.21–28 Thus, there is a balanced interplay between fungus virulence and host immunity in the vaginal mucosal environment, suggesting that commensalism results from such a balance.29,30 More detailed information about the epidemiology, diagnosis, current treatments of the infection, and recent studies for the development of protective vaccine are included in excellent reviews already published on this subject.3–11,31–42 Studies that evidence the role of virulence factors of Candida albicans in vaginal candidiasis The virulence factors of C. albicans that play a role in vaginal infections are: adherence, dimorphisms with antigenic variations, enzyme production, especially proteinase secretion and cell surface composition.23,25,43–45 Adherence is probably the first stage in mucocutaneous candidiasis; in fact, adherence of Candida cells to host cells, especially to epithelial cells, is essential for colonization, and it prevents or reduces the elimination of Candida by the host. Important is the role of mannoproteins for the attachment of Candida to epithelial cells. Several adhesins were isolated from C.albicans, molecules that promote Candida’s adhesion to host cells. Agglutinin-like sequence is a family of glycosylated proteins of C. albicans, homologues to S. cerevisiae agglutinins that are required for cell-cell recognition and contact during mating.46–49 Hyphal wall protein is a mannoprotein of the outer layer expanding an amino-terminal part and has the carboxy-linked part covalently bound to the B-glucan of the wall.50,51 Integrin like protein is a proteins similar to integrin which is a receptor present in important mammalian cells for binding cells with extra cellular protein matrices.52,53 Mannosyl transferase protein is a membrane protein with mannosyl transferase activity.54 That these proteins have an important role as adhesin and therefore initiating the colonization of the epithelium was highlighted because genes were cloned and constructed mutants with the two alleles destroyed and it was observed that the various mutants adhere with lesser entity in vitro and are less virulent in vivo.44,49,53 Adhesins play an important role in the pathogenesis of vaginal candidiasis by facilitating adherence to vaginal tissue.46,55–57 There is a clear evidence of the capacity of C. albicans to develop hyphae endowed with a multiplicity of immunoevasion mechanisms and greatly favoring implantation on the vaginal mucosa.58–63 Tissue sections of animal vaginas show that hyphae strongly adhere to the keratinized surface of the vaginal epithelium with some hyphal tips slightly infiltrating the subepithelial layer.64,65 There is a clear demonstration that each deletion of relevant genes affecting hyphal transition determine decrease or abolition of experimental pathogenicity.23,58 Strains of C. albicans that lack the capacity to undergo the dimorphic transition do not produce a biofilm and are typically nonpathogenic.66–69 Naglik and collaborators showed that the two forms of growth are discriminated by activation of distinct MAP kinase pathways.70 Enzyme secretion in particular aspartic proteinase (Sap), a family of at least 10 enzymes, plays a role in vaginal candidiasis. In fact, mutants of C. albicans with Sap1-3 gene deletion do not cause vaginal infection in rats and lose the capacity of damaging, in vitro, reconstituted human vaginal epithelium, in both studies pathogenicity was restored using fungal strains with relevant gene reintegrated.71,72 No such inference could be made with Sap4-6 deficient mutants, even when the triple mutant was used.71 Sap proteins cooperate, and sequential expression impacts virulence at different times during C. albicans infection.24,25 It has emerged that Sap2 protein plays a particularly consistent role in vaginal infection by C. albicans, probably as no other single virulence trait. In fact, Sap2 is the predominant enzyme in vaginal secretion of infected women and rats, and Sap2 gene was the first Sap gene that was seen to be expressed in vaginal infection.21,22,25 Moreover, Sap2 is the member of Sap family with the broadest substrate specificity. It is capable of hydrolyzing structural host proteins, such as keratin of the skin and the lining of the surface of the vaginal epithelium. Overall, the numerous studies on proteinase activity of C. albicans have been established that the Saps are indeed virulence factors with an important role in the pathogenesis of vaginal candidiasis.22,25,73,74 Studies of immune responses at vaginal level during Candida infection Mucosal colonization with C. albicans induces both antibody and cell mediated immunity. A successful host/Candida interaction that lead to a commensalism requires the coordinate actions of both innate and adaptive immune systems. In order to obtain possible insights into the host factors involved in the defense against vaginal candidiasis, we have long been employing a rat model of vaginal infection that has similarities to human disease, including the vaginal CD4/CD8 T-cell ratio.75 In this model, an initial self-healing infection confers a high degree of protection against subsequent reinfection by C. albicans.76 The protection is associated with the presence of protective antibodies against Candida constituents in the vaginal fluids and increased number of activated lymphocytes in the vaginal mucosa.77,78 Adoptive transfer of vaginal lymphocyte populations showed that distinct lymphocyte subsets participated in the adaptive anti-Candida immunity at vaginal level and demonstrated not only that CD4+ T cells were essential for protection but also the protective role of vaginal dendritic cells.79–81 To further investigate the host defense mechanisms at vaginal level, we evaluated the role of Toll-like receptors (TLRs) in protection against vaginal infection in mice with different TLR knocked out genes. TLR3 and TLR9 KO mice showed the kinetic of first infection similar to that of control mice. In contrast, TLR4 and the beta-glucan receptor Dectin-1 deficient mice were more susceptible to Candida infection. TLR 3 KO mice were only partially protected from the second Candida challenge. TLR9 KO mice were protected similar to control mice. The role of TLR 9 is not important in protection against vaginal candidiasis. In contrast, TLR 4 KO mice and dectin-1 KO mice were not protected from the second infection, a finding highlighting the requirement for TLR 4 and Dectin-1 in the acquired immunity to the fungus at the vaginal level. These results suggest that TLRs have a role in the innate and adaptive immunity to Candida at vaginal level. Of particular interest is the finding that TLR4 and Dectin-1 are both required for the induction of acquired protective immunity to the fungus.18,82 Resistance and tolerance mechanisms were both activated in murine VVC, involving interleukin (IL)-22 and IL-10–producing regulatory T cells, respectively, with a major contribution by the enzyme indoleamine 2,3-dioxygenase 1. Thus, IL-22 and IDO1 are crucial in balancing resistance with tolerance to Candida, their deficiencies are risk factors for RVVC.18 Studies to identify novel approach for vaccination or immunotherapy of vaginal candidiasis The defense mechanisms induced in the vagina during Candida infection evidenced in the animal model5,77–81 could lead to new strategies for vaccination or immunotherapy of vaginal candidiasis. In particular, in the rat model, we evaluated the effect of intravaginal immunization with recombinant secretory aspartyl proteinase (r-SAP-2). The animals immunized with r-Sap2 raised local anti-Sap2 immunoglobulin G (IgG) and immunoglobulin A (IgA) antibodies and were protected from the intravaginal challenge with C. albicans. Protection was likely due to the specific antibodies as shown by the passive transfer of immune vaginal fluid and the protective effects of passive vaccination with anti-Sap2 IgM and IgG monoclonal antibodies. Overall, the results evidenced that this recombinant proteinase constitutes a valuable reagent for use as a vaccine candidate for prevention and /or therapy against vaginal candidiasis.65,83 Then, the r-Sap2 was incorporated into influenza virosomes by Pevion, a Swiss biotech company. This novel vaccine, PEV7 (r-Sap2 virosomes), conferred protection to rats experimentally challenged with C. albicans, as exemplified by the accelerated clearance of the fungus from the vagina and resolution of the infection at least one week before infection in controls (administration of empty virosomes). The r-Sap2 virosomal vaccine generated a persistent protection from C. albicans after intravaginal immunization in rats. This long-lasting protective status was associated with persistence of anti-Sap2 antibodies in the rat vagina.84 Subsequently, Pevion conducted the PEV7 phase I study to assess the safety and immunogenicity in 48 healthy volunteers. The results demonstrated favorable safety and the generation of specific and functional B cell memory in 100% of the vaccinated women and were very encouraging with regards to the therapeutic potential of the vaccine (PEV7 clinical trial).85 NovaDigm Therapeutics Inc., a company developing innovative vaccines for fungal and bacterial infections, acquired the rights to r-Sap2 from Pevion and from Istituto Superiore di Sanità in Rome (Italian National Health Institute [ISS]). The company developed a vaccine containing the Als3 antigen (NDV-3), which facilitates Candida adherence to and invasion of human endothelial cells.86 The vaccine conferred protection to mice against experimental vaginal, oral, and intravenous challenge with C. albicans This vaccine is currently in the phase 1b/2a clinical study for the prevention of recurrent vulvovaginal candidiasis (NDV-3 clinical trial).87 Moreover, the company has acquired the rights to a hyphally regulated protein 1 (Hyr1) and to a β-mannan conjugate.88–90 The aim of NovaDigm company is to produce a multivalent vaccine that can induce an immune response against multiple virulence traits of Candida and can enhance the probability of success against C. albicans mucosal infections. The widespread occurrence of vaginal candidiasis and the development of resistance against antifungal agents has stimulated interest in understanding the pathogenesis of this disease. Sap activity has long enjoyed a putative role in Candida virulence. The data on SAP gene expression and the pathogenicity of SAP-deletion mutants have not only validated the previous predictions but have also greatly emphasised the general importance of this gene/enzyme family in the biology and pathogenicity of the fungus. The relationship between Saps and other putative virulence factors as hyphal and biofilm formation is an issue which needs to be addressed. Moreover, we investigate the immune response to Saps and the potential use of these responses to control Candida infections. Our observations with the rat vaginitis model have given evidence that the vaccine constituted of virosomal and Sap2 (PEV7) has an encouraging therapeutic potential for the treatment of recurrent vulvovaginal candidiasis. Several research teams developed anti-Candida vaccination.83,84,86,91–95 Two of these vaccines have passed phase 1 clinical trials for safety and immunogenicity, and one of them has entered a phase 2 clinical trial.85,87 Both vaccines evidenced protection in rat and mouse models of vaginal infection by C. albicans, although with a slightly different mechanism of immunological protection.31–36 It is hoped that, in a not too distant future, a safe and protective anti-Candida vaccine would improve the quality of life of the high number of women affected with RVVC. Acknowledgements The authors are grateful to Giuseppina Mandarino for assisting in the English of the final draft and to Alfredo Caggiano for help in manuscript preparation. Declaration of interest The authors report no conflicts of interest. The authors alone are responsible for the content and the writing of the paper. References 1. Sobel JD. Pathogenesis of recurrent vulvovaginal candidiasis. 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Medical Mycology – Oxford University Press
Published: Apr 1, 2018
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