title: Blastomyces dermatitidis serine protease dipeptidyl peptidase IVA (DppIVA) cleaves ELR+CXC chemokines altering their effects on neutrophils.
abstract: Blastomycosis elicits a pyogranulomatous inflammatory response that involves a prominent recruitment of neutrophils to the site of infection. Although neutrophils are efficiently recruited to the site of infection, this event is paradoxically coupled with the host's inability to control infection by Blastomyces dermatitidis, the causative agent. The mechanisms underlying this characteristic pyogranulomatous response and inability of neutrophils to kill the yeast are poorly understood. We recently reported that the fungal protease dipeptidyl peptidase IVA (DppIVA) promotes B. dermatitidis virulence by cleaving a dipeptide from the N-terminus of C-C chemokines and granulocyte/macrophage-colony stimulating factor, thereby inactivating them. Herein, we present evidence that DppIVA can also truncate the N-terminus of members of the ELR+CXC chemokine family, which are known to modulate neutrophil function. We show that the DppIVA cleaved form of human (h) CXCL-2, for example, hCXCL-2 (3-73), is a more potent neutrophil chemoattractant than its intact counterpart, but hCXCL-2 (3-73) is conversely impaired in its ability to prime the reactive oxygen species response of neutrophils. Thus, DppIVA action on ELR+CXC chemokines may promote the pyogranulomatous response that is typical of blastomycosis, while also explaining the inability of neutrophils to control infection.
authors.affiliation: Departments of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
authors.forename: Jenna
authors.initials: J
authors.lastname: Lorenzini
authors.affiliation: Departments of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
authors.forename: J
authors.initials: J
authors.lastname: Scott Fites
authors.affiliation: Department of Internal Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.|Department of Medical Microbiology and Immunology, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
authors.forename: Jeniel
authors.initials: J
authors.lastname: Nett
authors.affiliation: Departments of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.|Department of Internal Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.|Department of Medical Microbiology and Immunology, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
authors.forename: Bruce S
authors.identifier: 0000-0003-3212-1539
authors.initials: BS
authors.lastname: Klein
mesh_terms: D000818:Animals; D001758:Blastomyces / Q000201:enzymology / Q000276:immunology*; D001759:Blastomycosis / Q000276:immunology* / Q000382:microbiology; D002478:Cells, Cultured; D054360:Chemokine CXCL1 / Q000378:metabolism*; D054426:Chemokine CXCL2 / Q000378:metabolism*; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / Q000378:metabolism*; D006801:Humans; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000276:immunology*; D017382:Reactive Oxygen Species / Q000276:immunology
chemical_list: D054360:Chemokine CXCL1; D054426:Chemokine CXCL2; C475895:Cxcl1 protein, mouse; C404915:Cxcl2 protein, mouse; D017382:Reactive Oxygen Species; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse