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 elaborate dipeptidylpeptidase 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 of form of molecular piracy by a broadly conserved aminopeptidase during disease pathogenesis.

Graphical abstract

eTOC BLURB

Mammalian proteases regulate the immune response by altering the activity of cytokines and chemokines. Here, Sterkel, Lorenzini and colleagues identify a fungal protease that promotes virulence and suppresses innate immunity to infection by mimicking the immune-modulatory activity of its mammalian counterpart.