title: Fungal Mimicry of a Mammalian Aminopeptidase Disables Innate Immunity and Promotes Pathogenicity.
abstract: Systemic fungal infections trigger marked immune-regulatory disturbances, but the mechanisms are poorly understood. We report that the pathogenic yeast of Blastomyces dermatitidis elaborates dipeptidyl-peptidase IVA (DppIVA), a close mimic of the mammalian ectopeptidase CD26, which modulates critical aspects of hematopoiesis. We show that, like the mammalian enzyme, fungal DppIVA cleaved C-C chemokines and GM-CSF. Yeast producing DppIVA crippled the recruitment and differentiation of monocytes and prevented phagocyte activation and ROS production. Silencing fungal DppIVA gene expression curtailed virulence and restored recruitment of CCR2(+) monocytes, generation of TipDC, and phagocyte killing of yeast. Pharmacological blockade of DppIVA restored leukocyte effector functions and stemmed infection, while addition of recombinant DppIVA to gene-silenced yeast enabled them to evade leukocyte defense. Thus, fungal DppIVA mediates immune-regulatory disturbances that underlie invasive fungal disease. These findings reveal a form of molecular piracy by a broadly conserved aminopeptidase during disease pathogenesis.
authors.affiliation: Departments of Pediatrics, Medicine, and Medical Microbiology and Immunology, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53726, USA.
authors.forename: Alana K
authors.initials: AK
authors.lastname: Sterkel
authors.affiliation: Departments of Pediatrics, Medicine, and Medical Microbiology and Immunology, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53726, USA.
authors.forename: Jenna L
authors.initials: JL
authors.lastname: Lorenzini
authors.affiliation: Departments of Pediatrics, Medicine, and Medical Microbiology and Immunology, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53726, USA.
authors.forename: J Scott
authors.initials: JS
authors.lastname: Fites
authors.affiliation: Division of Infectious Disease, University of Cincinnati College of Medicine and Veterans Affairs Hospital, Cincinnati, OH 45220, USA.
authors.forename: Kavitha
authors.initials: K
authors.lastname: Subramanian Vignesh
authors.affiliation: Departments of Pediatrics, Medicine, and Medical Microbiology and Immunology, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53726, USA.
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Sullivan
authors.affiliation: Departments of Pediatrics, Medicine, and Medical Microbiology and Immunology, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53726, USA.
authors.forename: Marcel
authors.initials: M
authors.lastname: Wuthrich
authors.affiliation: Departments of Pediatrics, Medicine, and Medical Microbiology and Immunology, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53726, USA.
authors.forename: Tristan
authors.initials: T
authors.lastname: Brandhorst
authors.affiliation: Departments of Pediatrics, Medicine, and Medical Microbiology and Immunology, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53726, USA.
authors.forename: Nydiaris
authors.initials: N
authors.lastname: Hernandez-Santos
authors.affiliation: Division of Infectious Disease, University of Cincinnati College of Medicine and Veterans Affairs Hospital, Cincinnati, OH 45220, USA.
authors.forename: George S
authors.initials: GS
authors.lastname: Deepe
authors.affiliation: Departments of Pediatrics, Medicine, and Medical Microbiology and Immunology, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53726, USA. Electronic address: bsklein@wisc.edu.
authors.forename: Bruce S
authors.initials: BS
authors.lastname: Klein
mesh_terms: D000626:Aminopeptidases / Q000378:metabolism*; D000818:Animals; D000067558:Biological Mimicry; D001758:Blastomyces / Q000201:enzymology* / Q000472:pathogenicity; D018925:Chemokines / Q000378:metabolism; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / Q000235:genetics / Q000378:metabolism*; D020868:Gene Silencing; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D057131:Immune Evasion; D007108:Immune Tolerance; D007113:Immunity, Innate / Q000187:drug effects*; D008264:Macrophages / Q000276:immunology; D051379:Mice; D050296:Microbial Viability; D009000:Monocytes / Q000276:immunology; D010587:Phagocytosis; D017382:Reactive Oxygen Species / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D037521:Virulence Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D018925:Chemokines; D017382:Reactive Oxygen Species; D037521:Virulence Factors; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D000626:Aminopeptidases; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases
keywords: DppIV; TipDCs; fungal; macrophages; neutrophils