title: Immunomodulatory metabolites released by the frog-killing fungus Batrachochytrium dendrobatidis.
abstract: Batrachochytrium dendrobatidis is a fungal pathogen in the phylum Chytridiomycota that causes the skin disease chytridiomycosis. Chytridiomycosis is considered an emerging infectious disease linked to worldwide amphibian declines and extinctions. Although amphibians have well-developed immune defenses, clearance of this pathogen from the skin is often impaired. Previously, we showed that the adaptive immune system is involved in the control of the pathogen, but B. dendrobatidis releases factors that inhibit in vitro and in vivo lymphocyte responses and induce lymphocyte apoptosis. Little is known about the nature of the inhibitory factors released by this fungus. Here, we describe the isolation and characterization of three fungal metabolites produced by B. dendrobatidis but not by the closely related nonpathogenic chytrid Homolaphlyctis polyrhiza. These metabolites are methylthioadenosine (MTA), tryptophan, and an oxidized product of tryptophan, kynurenine (Kyn). Independently, both MTA and Kyn inhibit the survival and proliferation of amphibian lymphocytes and the Jurkat human T cell leukemia cell line. However, working together, they become effective at much lower concentrations. We hypothesize that B. dendrobatidis can adapt its metabolism to release products that alter the local environment in the skin to inhibit immunity and enhance the survival of the pathogen.
authors.affiliation: Department of Pathology, Microbiology, and Immunology, and Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, Tennessee, USA Department of Biological Sciences, Vanderbilt University, Nashville, Tennessee, USA louise.rollins-smith@vanderbilt.edu.
authors.forename: Louise A
authors.initials: LA
authors.lastname: Rollins-Smith
authors.affiliation: Department of Biological Sciences, Vanderbilt University, Nashville, Tennessee, USA.
authors.forename: J Scott
authors.initials: JS
authors.lastname: Fites
authors.affiliation: Department of Pathology, Microbiology, and Immunology, and Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
authors.forename: Laura K
authors.initials: LK
authors.lastname: Reinert
authors.affiliation: Department of Biological Sciences, Vanderbilt University, Nashville, Tennessee, USA.
authors.forename: Andrea R
authors.initials: AR
authors.lastname: Shiakolas
authors.affiliation: Division of Natural and Computational Sciences, Gwynedd Mercy University, Gwynedd Valley, Pennsylvania, USA.
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Umile
authors.affiliation: Department of Chemistry, Villanova University, Villanova, Pennsylvania, USA.
authors.forename: Kevin P C
authors.initials: KP
authors.lastname: Minbiole
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives* / Q000096:biosynthesis / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D008411:Chytridiomycota / Q000276:immunology / Q000378:metabolism / Q000472:pathogenicity*; D004357:Drug Synergism; D054884:Host-Pathogen Interactions / Q000276:immunology; D006801:Humans; D019169:Jurkat Cells; D007737:Kynurenine / Q000096:biosynthesis / Q000494:pharmacology*; D008214:Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D009181:Mycoses / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D012867:Skin / Q000187:drug effects / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D013872:Thionucleosides / Q000096:biosynthesis / Q000494:pharmacology*; D014364:Tryptophan / Q000096:biosynthesis / Q000494:pharmacology*; D014982:Xenopus laevis
chemical_list: D013872:Thionucleosides; D007737:Kynurenine; C021714:2-methylthioadenosine; D014364:Tryptophan; D000241:Adenosine