Title: Fungal Mimicry of a Mammalian Aminopeptidase Disables Innate Immunity and Promotes Pathogenicity.
Authors: Sterkel, Alana K; Lorenzini, Jenna L; Fites, J Scott; Subramanian Vignesh, Kavitha; Sullivan, Thomas D; Wuthrich, Marcel; Brandhorst, Tristan; Hernandez-Santos, Nydiaris; Deepe Jr, George S; Klein, Bruce S
Published In Cell Host Microbe, (2016 Mar 09)
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.
PubMed ID: 26922990
MeSH Terms: Aminopeptidases/metabolism*; Animals; Biological Mimicry; Blastomyces/enzymology*; Blastomyces/pathogenicity; Chemokines/metabolism; Dipeptidyl-Peptidases and Tripeptidyl-Peptidases/genetics; Dipeptidyl-Peptidases and Tripeptidyl-Peptidases/metabolism*; Gene Silencing; Granulocyte-Macrophage Colony-Stimulating Factor/metabolism; Immune Evasion*; Immune Tolerance*; Immunity, Innate/drug effects*; Macrophages/immunology; Mice; Microbial Viability; Monocytes/immunology; Phagocytosis; Reactive Oxygen Species/metabolism; Sequence Homology, Amino Acid; Virulence Factors/genetics; Virulence Factors/metabolism*