title: Inactivation of the antifungal and immunomodulatory properties of human cathelicidin LL-37 by aspartic proteases produced by the pathogenic yeast Candida albicans.
abstract: Constant cross talk between Candida albicans yeast cells and their human host determines the outcome of fungal colonization and, eventually, the progress of infectious disease (candidiasis). An effective weapon used by C. albicans to cope with the host defense system is the release of 10 distinct secreted aspartic proteases (SAPs). Here, we validate a hypothesis that neutrophils and epithelial cells use the antimicrobial peptide LL-37 to inactivate C. albicans at sites of candidal infection and that C. albicans uses SAPs to effectively degrade LL-37. LL-37 is cleaved into multiple products by SAP1 to -4, SAP8, and SAP9, and this proteolytic processing is correlated with the gradual decrease in the antifungal activity of LL-37. Moreover, a major intermediate of LL-37 cleavage-the LL-25 peptide-is antifungal but devoid of the immunomodulatory properties of LL-37. In contrast to LL-37, LL-25 did not affect the generation of reactive oxygen species by neutrophils upon treatment with phorbol esters. Stimulating neutrophils with LL-25 (rather than LL-37) significantly decreased calcium flux and interleukin-8 production, resulting in lower chemotactic activity of the peptide against neutrophils, which may decrease the recruitment of neutrophils to infection foci. LL-25 also lost the function of LL-37 as an inhibitor of neutrophil apoptosis, thereby reducing the life span of these defense cells. This study indicates that C. albicans can effectively use aspartic proteases to destroy the antimicrobial and immunomodulatory properties of LL-37, thus enabling the pathogen to survive and propagate.
authors.affiliation: Department of Analytical Biochemistry, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University in Krakow, Krakow, Poland maria.rapala-kozik@uj.edu.pl.
authors.forename: Maria
authors.initials: M
authors.lastname: Rapala-Kozik
authors.affiliation: Department of Analytical Biochemistry, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University in Krakow, Krakow, Poland.
authors.forename: Oliwia
authors.initials: O
authors.lastname: Bochenska
authors.affiliation: Department of Analytical Biochemistry, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University in Krakow, Krakow, Poland.
authors.forename: Marcin
authors.initials: M
authors.lastname: Zawrotniak
authors.affiliation: Department of Analytical Biochemistry, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University in Krakow, Krakow, Poland.
authors.forename: Natalia
authors.initials: N
authors.lastname: Wolak
authors.affiliation: Department of Analytical Biochemistry, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University in Krakow, Krakow, Poland.
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Trebacz
authors.affiliation: Department of Analytical Biochemistry, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University in Krakow, Krakow, Poland.
authors.forename: Mariusz
authors.initials: M
authors.lastname: Gogol
authors.affiliation: Department of Analytical Biochemistry, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University in Krakow, Krakow, Poland.
authors.forename: Dominika
authors.initials: D
authors.lastname: Ostrowska
authors.affiliation: Department of Applied Physics, Graduate School of Engineering, Osaka University, Suita, Osaka, Japan.
authors.forename: Wataru
authors.initials: W
authors.lastname: Aoki
authors.affiliation: Division of Applied Life Sciences, Graduate School of Agriculture, Kyoto University, Sakyo-ku, Kyoto, Japan.
authors.forename: Mitsuyoshi
authors.initials: M
authors.lastname: Ueda
authors.affiliation: Department of Analytical Biochemistry, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University in Krakow, Krakow, Poland.
authors.forename: Andrzej
authors.initials: A
authors.lastname: Kozik
mesh_terms: D000595:Amino Acid Sequence; D000935:Antifungal Agents / Q000378:metabolism / Q000494:pharmacology*; D023181:Antimicrobial Cationic Peptides / Q000378:metabolism* / Q000494:pharmacology*; D057055:Aspartic Acid Proteases / Q000378:metabolism*; D002176:Candida albicans / Q000201:enzymology*; D020169:Caspases / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects; D018920:Coculture Techniques; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation; D006801:Humans; D007155:Immunologic Factors / Q000378:metabolism / Q000494:pharmacology*; D009504:Neutrophils / Q000166:cytology / Q000502:physiology; D017382:Reactive Oxygen Species / Q000378:metabolism; D023063:Receptors, Interleukin-8B / Q000235:genetics / Q000378:metabolism; D054804:Cathelicidins
chemical_list: D000935:Antifungal Agents; D023181:Antimicrobial Cationic Peptides; D007155:Immunologic Factors; D017382:Reactive Oxygen Species; D023063:Receptors, Interleukin-8B; D057055:Aspartic Acid Proteases; D020169:Caspases; D054804:Cathelicidins
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