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      Candidalysin: discovery and function in Candida albicans infections

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          Abstract

          Candidalysin is a cytolytic peptide toxin secreted by the invasive form of the human pathogenic fungus, Candida albicans. Candidalysin is critical for mucosal and systemic infections and is a key driver of host cell activation, neutrophil recruitment and Type 17 immunity. Candidalysin is regarded as the first true classical virulence factor of C. albicans but also triggers protective immune responses. This review will discuss how candidalysin was discovered, the mechanisms by which this peptide toxin contributes to C. albicans infections, and how its discovery has advanced our understanding of fungal pathogenesis and disease.

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          Candidalysin is a fungal peptide toxin critical for mucosal infection

          David Moyes, Duncan Wilson, Jonathan Richardson … (2016)
          Cytolytic proteins and peptide toxins are classical virulence factors of several bacterial pathogens which disrupt epithelial barrier function, damage cells and activate or modulate host immune responses. Until now human pathogenic fungi were not known to possess such toxins. Here we identify the first fungal cytolytic peptide toxin in the opportunistic pathogen Candida albicans. This secreted toxin directly damages epithelial membranes, triggers a danger response signaling pathway and activates epithelial immunity. Toxin-mediated membrane permeabilization is enhanced by a positively charged C-terminus and triggers an inward current concomitant with calcium influx. C. albicans strains lacking this toxin do not activate or damage epithelial cells and are avirulent in animal models of mucosal infection. We propose the name ‘Candidalysin’ for this cytolytic peptide toxin; a newly identified, critical molecular determinant of epithelial damage and host recognition of the clinically important fungus, C. albicans.
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            Th17 cells and IL-17 receptor signaling are essential for mucosal host defense against oral candidiasis

            Heather Conti, Fang-Fang Shen, Namrata Nayyar … (2009)
            The commensal fungus Candida albicans causes oropharyngeal candidiasis (OPC; thrush) in settings of immunodeficiency. Although disseminated, vaginal, and oral candidiasis are all caused by C. albicans species, host defense against C. albicans varies by anatomical location. T helper 1 (Th1) cells have long been implicated in defense against candidiasis, whereas the role of Th17 cells remains controversial. IL-17 mediates inflammatory pathology in a gastric model of mucosal candidiasis, but is host protective in disseminated disease. Here, we directly compared Th1 and Th17 function in a model of OPC. Th17-deficient (IL-23p19−/−) and IL-17R–deficient (IL-17RA−/−) mice experienced severe OPC, whereas Th1-deficient (IL-12p35−/−) mice showed low fungal burdens and no overt disease. Neutrophil recruitment was impaired in IL-23p19−/− and IL-17RA−/−, but not IL-12−/−, mice, and TCR-αβ cells were more important than TCR-γδ cells. Surprisingly, mice deficient in the Th17 cytokine IL-22 were only mildly susceptible to OPC, indicating that IL-17 rather than IL-22 is vital in defense against oral candidiasis. Gene profiling of oral mucosal tissue showed strong induction of Th17 signature genes, including CXC chemokines and β defensin-3. Saliva from Th17-deficient, but not Th1-deficient, mice exhibited reduced candidacidal activity. Thus, the Th17 lineage, acting largely through IL-17, confers the dominant response to oral candidiasis through neutrophils and antimicrobial factors.
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              Syk kinase signalling couples to the Nlrp3 inflammasome for anti-fungal host defence.

              Olaf Gross, Hendrik Poeck, Michael Bscheider … (2009)
              Fungal infections represent a serious threat, particularly in immunocompromised patients. Interleukin-1beta (IL-1beta) is a key pro-inflammatory factor in innate antifungal immunity. The mechanism by which the mammalian immune system regulates IL-1beta production after fungal recognition is unclear. Two signals are generally required for IL-1beta production: an NF-kappaB-dependent signal that induces the synthesis of pro-IL-1beta (p35), and a second signal that triggers proteolytic pro-IL-1beta processing to produce bioactive IL-1beta (p17) via Caspase-1-containing multiprotein complexes called inflammasomes. Here we demonstrate that the tyrosine kinase Syk, operating downstream of several immunoreceptor tyrosine-based activation motif (ITAM)-coupled fungal pattern recognition receptors, controls both pro-IL-1beta synthesis and inflammasome activation after cell stimulation with Candida albicans. Whereas Syk signalling for pro-IL-1beta synthesis selectively uses the Card9 pathway, inflammasome activation by the fungus involves reactive oxygen species production and potassium efflux. Genetic deletion or pharmalogical inhibition of Syk selectively abrogated inflammasome activation by C. albicans but not by inflammasome activators such as Salmonella typhimurium or the bacterial toxin nigericin. Nlrp3 (also known as NALP3) was identified as the critical NOD-like receptor family member that transduces the fungal recognition signal to the inflammasome adaptor Asc (Pycard) for Caspase-1 (Casp1) activation and pro-IL-1beta processing. Consistent with an essential role for Nlrp3 inflammasomes in antifungal immunity, we show that Nlrp3-deficient mice are hypersusceptible to Candida albicans infection. Thus, our results demonstrate the molecular basis for IL-1beta production after fungal infection and identify a crucial function for the Nlrp3 inflammasome in mammalian host defence in vivo.
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                Author and article information

                Journal
                Journal ID (nlm-journal-id): 9815056
                Journal ID (nlm-ta): Curr Opin Microbiol
                Journal ID (iso-abbrev): Curr. Opin. Microbiol.
                Title: Current opinion in microbiology
                ISSN (Print): 1369-5274
                ISSN (Electronic): 1879-0364
                Publication date (Print): 06 July 2019
                Publication date (Electronic): 06 July 2019
                Publication date Nihms-submitted: 30 July 2019
                Publication date PMC-release: 08 August 2019
                Volume: 52
                Pages: 100-109
                Affiliations
                [1 ]Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral & Craniofacial Sciences, King’s College London, London, SE1 1UL, United Kingdom
                [2 ]Division of Rheumatology and Clinical Immunology, University of Pittsburgh, Pittsburgh PA 15261, USA
                [3 ]Department of Microbial Pathogenicity Mechanisms, Leibniz Institute for Natural Product Research and Infection Biology (HKI), Jena, 07745, Germany
                [4 ]Friedrich Schiller University, Jena, 07745, Germany
                Author notes
                Corresponding author: Naglik, Julian R ( julian.naglik@ 123456kcl.ac.uk )

                This review comes from a themed issue on Host-microbe interactions: fungi

                Edited by Chad A Rappleye and Duncan Wilson

                Article
                Manuscript ID: EMS83881
                DOI: 10.1016/j.mib.2019.06.002
                PMC ID: 6687503
                PubMed ID: 31288097
                SO-VID: bcdd9424-f397-440c-a3bd-191ca3ab0806
                License:

                This is an open access article under the CC BY license ( http://creativecommons.org/licenses/by/4.0/).

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                ScienceOpen disciplines: Microbiology & Virology
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                ScienceOpen disciplines: Microbiology & Virology

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