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.
journal_name
Cell Host Microbejournal_title
Cell host & microbeauthors
Sterkel AK,Lorenzini JL,Fites JS,Subramanian Vignesh K,Sullivan TD,Wuthrich M,Brandhorst T,Hernandez-Santos N,Deepe GS Jr,Klein BSdoi
10.1016/j.chom.2016.02.001subject
Has Abstractpub_date
2016-03-09 00:00:00pages
361-74issue
3eissn
1931-3128issn
1934-6069pii
S1931-3128(16)30016-6journal_volume
19pub_type
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