Immunotherapy of Candida spp.-caused infections: myth or reality?

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Candidiasis is a mycosis caused by opportunistic pathogenic Candida spp. fungi. The infectious process can manifest as superficial forms affecting the skin and mucous membranes, as well as invasive variants. Since Candida spp. are commensals, a related disease development implies an imbalance between the pathogenic fungal factors and human immune system. Research in the field of immunotherapy of fungal infections is particularly relevant due to the increasing resistance to antifungal drugs. Based on the analyzed publications investigating candidiasis immunotherapy retrieved from the databases PubMed, ClinicalKey, and e-library, we have assessed the main directions and achievements in immunotherapy of infections caused by Candida spp., described emerging issues, and outlined future prospects. The development of live vaccines based on attenuated, genetically modified, and mutant Candida strains began in the 1980s and continues to the present day. However, creating vaccines based on Candida recombinant proteins, adhesins, and enzymes represents a safer alternative to live vaccines. A promising direction is the development of conjugate vaccines, in which the fusion of weaker antigens (cell wall glycans) with carrier immunogenic proteins leads to the formation of immunogens capable of eliciting a robust immune response. In experiments, vaccines based on inactivated C. аlbicans along with a genetically Escherichia coli-derived modified heat-labile toxin as an adjuvant have also been studied. The experience of creating combination therapies aimed at combating recurrent bacterial and fungal urogenital tract infections is promising, e.g., the combination of sublingual inactivated polyvalent bacterial vaccine MV140 and sublingual preparation of inactivated Candida albicans V132. An interesting approach involves the use of inactivated S. cerevisiae yeasts, providing cross-protection against infections caused by C. аlbicans, Aspergillus fumigatus, and Coccidioides posadasii. A search for immunotherapy targets continues, with numerous studies aimed at a deeper understanding of crosstalk between C. аlbicans and human host. Currently, two recombinant vaccines (PEV7 and NDV-3) have successfully completed Phase I/II clinical trials, raising hopes for their clinical use in the near future.

作者简介

Sofia Khostelidi

North-Western State Medical University named after I.I. Mechnikov

编辑信件的主要联系方式.
Email: Sofya.Khostelidi@szgmu.ru

DSc (Medicine), Associate Professor, Associate Professor of the Department of Clinical Mycology, Allergology and Immunology

俄罗斯联邦, St. Petersburg

N. Serebryanaya

North-Western State Medical University named after I.I. Mechnikov; Institute of Experimental Medicine; St. Petersburg State University

Email: Sofya.Khostelidi@szgmu.ru

DSc (Medicine), Professor, Professor of the Department of Clinical Mycology, Allergology and Immunology; Head of the Laboratory of General Immunology, Department of General Pathology and Pathophysiology; Professor of the Department of Cytology and Histology

俄罗斯联邦, St. Petersburg; St. Petersburg; St. Petersburg

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2. Figure 1. Immune responses induced by Candida antigens. Adapted from [36]. Comments. Epithelial barrier builds up the first line defense against Candida. Epithelial cells produce antimicrobial peptides restraining Candida growth. The level of antimicrobial peptide production depends on T helper 17 (TH17) cell-released IL-17 and IL-22. When the epithelial barrier becomes damaged, fungal antigens (PAMPs) interact with dendritic cell (DC) PRRs (TLRs, dectins, galectin-3, mannose receptors, DC-SIGN and Mincle) followed by DC maturation promoting antigen presentation to activate naive CD4+ T cells via MHC class II molecules and costimulatory CD40-CD40L (CD154). DCs produce cytokines that control formation of specific T cell subsets. For example, IL-23, IL-6, and TGF-β skew towards Th17 (signature cytokines: IL-17 and IL-21) mainly involved in inflammatory response. Activated CD4+ T cells interact with B cells to elicit production of antibodies of various isotypes with high affinity and long half-life. B cell response to non-protein antigens (polysaccharides, lipids, glycolipids, nucleic acids) occurs without T cell help (T-independent response) not resulting in emerging immunological memory and, subsequently, no secondary response, featured solely with low affinity short half-life IgM antibodies. Research into development of Candida (subunit and conjugate) vaccines is aimed at developing a T-dependent immune response by binding fungal polysaccharides to various carrier proteins.

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