title: Caspofungin modulates inflammatory responses to Aspergillus fumigatus through stage-specific effects on fungal beta-glucan exposure.
abstract: Echinocandins target fungal beta-1,3 glucan synthesis and are used clinically to treat invasive aspergillosis. Although echinocandins do not completely inhibit in vitro growth of Aspergillus fumigatus, they do induce morphological changes in fungal hyphae. Because beta-1,3 glucans activate host antifungal pathways via the Dectin-1 receptor, we investigated the effect of echinocandins on inflammatory responses to A. fumigatus. Caspofungin- or micafungin-treated conidia and germlings induced less secretion of tumor necrosis factor (TNF) and CXCL2 by macrophages than did their untreated counterparts. Diminished secretion of TNF and CXCL2 correlated with diminished beta-glucan exposure on echinocandin-treated germ tubes. In contrast to treated conidia and germlings, echinocandin-treated hyphae stimulated increased release of TNF and CXCL2 by macrophages and demonstrated intense staining with a beta-glucan-specific antibody, particularly at hyphal tips. Our experiments demonstrate that echinocandin-induced morphological changes in A. fumigatus hyphae are accompanied by increased beta-glucan exposure, with consequent increases in Dectin-1-mediated inflammatory responses by macrophages.
authors.affiliation: Infectious Diseases Service, Memorial Sloan-Kettering Cancer Center and Immunology Program, Sloan-Kettering Institute, New York 10021, USA. hohlt@mskcc.org
authors.forename: T M
authors.initials: TM
authors.lastname: Hohl
authors.forename: M
authors.initials: M
authors.lastname: Feldmesser
authors.forename: D S
authors.initials: DS
authors.lastname: Perlin
authors.forename: E G
authors.initials: EG
authors.lastname: Pamer
mesh_terms: D000935:Antifungal Agents / Q000627:therapeutic use*; D001228:Aspergillosis / Q000188:drug therapy*; D001232:Aspergillus fumigatus / Q000187:drug effects* / Q000254:growth & development / Q000502:physiology; D002176:Candida albicans / Q000187:drug effects; D000077336:Caspofungin; D054426:Chemokine CXCL2 / Q000187:drug effects / Q000378:metabolism; D054714:Echinocandins / Q000627:therapeutic use*; D006801:Humans; D007249:Inflammation / Q000188:drug therapy* / Q000382:microbiology*; D055666:Lipopeptides; D018613:Microscopy, Confocal; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D047071:beta-Glucans / Q000378:metabolism*
chemical_list: D000935:Antifungal Agents; D054426:Chemokine CXCL2; D054714:Echinocandins; D055666:Lipopeptides; D014409:Tumor Necrosis Factor-alpha; D047071:beta-Glucans; D000077336:Caspofungin