title: The WI-1 adhesin blocks phagocyte TNF-alpha production, imparting pathogenicity on Blastomyces dermatitidis.
abstract: The WI-1 adhesin is indispensable for pathogenicity of Blastomyces dermatitidis and is thought to promote pulmonary infection by fixing yeast to lung tissue and cells. Recent findings suggest that WI-1 confers pathogenicity by mechanisms in addition to adherence. Here, we investigated whether WI-1 modulates host immunity by altering production of pro-inflammatory cytokines. Production of TNF-alpha in lung alveolar fluids of mice infected with B. dermatitidis was severalfold higher for WI-1 knockout yeast compared with wild-type yeast, and in vitro coculture of unseparated lung cells with these isogenic yeast disclosed similar differences. Upon coculture with purified macrophages and neutrophils, wild-type yeast blocked TNF-alpha production, yet WI-1 knockout yeast stimulated production. Coating knockout yeast with purified WI-1 converted them from stimulating TNF-alpha production to inhibiting production. Addition of purified WI-1 into stimulated phagocyte cultures led to concentration-dependent inhibition of TNF-alpha production. Neutralization of TNF-alpha in vivo exacerbated experimental pulmonary infection, particularly for the nonpathogenic WI-1 knockout yeast. Inducing increased TNF-alpha levels in the lung by adenovirus-vectored gene therapy controlled infection with wild-type yeast. Thus, the WI-1 adhesin on yeast modulates host immunity through blocking TNF-alpha production by phagocytes, which fosters progression of pulmonary infection.
authors.affiliation: Department of Pediatrics, Comprehensive Cancer Center, University of Wisconsin Medical School, University of Wisconsin Hospital and Clinics, Madison, WI, USA.
authors.forename: B
authors.initials: B
authors.lastname: Finkel-Jimenez
authors.forename: M
authors.initials: M
authors.lastname: Wüthrich
authors.forename: T
authors.initials: T
authors.lastname: Brandhorst
authors.forename: B S
authors.initials: BS
authors.lastname: Klein
mesh_terms: D000256:Adenoviridae / Q000235:genetics / Q000276:immunology; D000818:Animals; D001758:Blastomyces / Q000235:genetics / Q000276:immunology* / Q000472:pathogenicity*; D001759:Blastomycosis / Q000276:immunology / Q000382:microbiology / Q000628:therapy; D002448:Cell Adhesion / Q000276:immunology; D002478:Cells, Cultured; D005656:Fungal Proteins / Q000235:genetics / Q000378:metabolism / Q000633:toxicity*; D015316:Genetic Therapy; D006023:Glycoproteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism / Q000633:toxicity*; D007442:Intubation, Intratracheal; D016676:Macrophages, Alveolar / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D017737:Macrophages, Peritoneal / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D010587:Phagocytosis / Q000235:genetics / Q000276:immunology*; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000627:therapeutic use; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology
chemical_list: D005656:Fungal Proteins; D006023:Glycoproteins; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha