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      Recurrent Vulvovaginal Candidiasis: An Immunological Perspective

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          Abstract

          Vulvovaginal candidiasis (VVC) is a widespread vaginal infection primarily caused by Candida albicans. VVC affects up to 75% of women of childbearing age once in their life, and up to 9% of women in different populations experience more than three episodes per year, which is defined as recurrent vulvovaginal candidiasis (RVVC). RVVC results in diminished quality of life as well as increased associated healthcare costs. For a long time, VVC has been considered the outcome of inadequate host defenses against Candida colonization, as in the case of primary immunodeficiencies associated with persistent fungal infections and insufficient clearance. Intensive research in recent decades has led to a new hypothesis that points toward a local mucosal overreaction of the immune system rather than a defective host response to Candida colonization. This review provides an overview of the current understanding of the host immune response in VVC pathogenesis and suggests that a tightly regulated fungus–host–microbiota interplay might exert a protective role against recurrent Candida infections.

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          Most cited references115

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          Vulvovaginal candidosis.

          Despite therapeutic advances, vulvovaginal candidosis remains a common problem worldwide, affecting all strata of society. Understanding of anti-candida host defence mechanisms in the vagina has developed slowly and, despite a growing list of recognised risk factors, a fundamental grasp of pathogenic mechanisms continues to elude us. The absence of rapid, simple, and inexpensive diagnostic tests continues to result in both overdiagnosis and underdiagnosis of vulvovaginal candidosis. I review the epidemiology and pathogenesis of this infection, and also discuss management strategies.
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            Dectin-1 is required for beta-glucan recognition and control of fungal infection.

            Beta-glucan is one of the most abundant polysaccharides in fungal pathogens, yet its importance in antifungal immunity is unclear. Here we show that deficiency of dectin-1, the myeloid receptor for beta-glucan, rendered mice susceptible to infection with Candida albicans. Dectin-1-deficient leukocytes demonstrated significantly impaired responses to fungi even in the presence of opsonins. Impaired leukocyte responses were manifested in vivo by reduced inflammatory cell recruitment after fungal infection, resulting in substantially increased fungal burdens and enhanced fungal dissemination. Our results establish a fundamental function for beta-glucan recognition by dectin-1 in antifungal immunity and demonstrate a signaling non-Toll-like pattern-recognition receptor required for the induction of protective immune responses.
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              A homozygous CARD9 mutation in a family with susceptibility to fungal infections.

              Chronic mucocutaneous candidiasis may be manifested as a primary immunodeficiency characterized by persistent or recurrent infections of the mucosa or the skin with candida species. Most cases are sporadic, but both autosomal dominant inheritance and autosomal recessive inheritance have been described. We performed genetic studies in 36 members of a large, consanguineous five-generation family, in which 4 members had recurrent fungal infections and an additional 3 members died during adolescence, 2 after invasive infection of the brain with candida species. All 36 family members were enrolled in the study, and 22 had blood samples taken for DNA analysis. Homozygosity mapping was used to locate the mutated gene. In the 4 affected family members (patients) and the 18 unaffected members we sequenced CARD9, the gene encoding the caspase recruitment domain-containing protein 9, carried out T-cell phenotyping, and performed functional studies, with the use of either leukocytes from the patients or a reconstituted murine model of the genetic defect. We found linkage (lod score, 3.6) to a genomic interval on chromosome 9q, including CARD9. All four patients had a homozygous point mutation in CARD9, resulting in a premature termination codon (Q295X). Healthy family members had wild-type expression of the CARD9 protein; the four patients lacked wild-type expression, which was associated with low numbers of Th17 cells (helper T cells producing interleukin-17). Functional studies based on genetic reconstitution of myeloid cells from Card9(-/-) mice showed that the Q295X mutation impairs innate signaling from the antifungal pattern-recognition receptor dectin-1. An autosomal recessive form of susceptibility to chronic mucocutaneous candidiasis is associated with homozygous mutations in CARD9. 2009 Massachusetts Medical Society
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                Author and article information

                Journal
                Microorganisms
                Microorganisms
                microorganisms
                Microorganisms
                MDPI
                2076-2607
                21 January 2020
                February 2020
                : 8
                : 2
                : 144
                Affiliations
                [1 ]Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands; diletta.rosati@ 123456radboudumc.nl (D.R.); mariolina.bruno@ 123456radboudumc.nl (M.B.); Martin.Jaeger@ 123456radboudumc.nl (M.J.); Jaap.tenOever@ 123456radboudumc.nl (J.t.O.)
                [2 ]Department for Genomics & Immunoregulation, Life and Medical Sciences Institute (LIMES), University of Bonn, 53115 Bonn, Germany
                Author notes
                Author information
                https://orcid.org/0000-0003-2992-2503
                https://orcid.org/0000-0002-5353-7691
                Article
                microorganisms-08-00144
                10.3390/microorganisms8020144
                7074770
                31972980
                c109d452-bb37-43e1-acf7-fa31206e67d6
                © 2020 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 19 December 2019
                : 17 January 2020
                Categories
                Review

                vulvovaginal candidiasis,recurrent vulvovaginal candidiasis,candida albicans,host immune response,immunity,fungal infections

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