title: Analysis of non-adhesive pathogenic mechanisms of BAD1 on Blastomyces dermatitidis.
abstract: The adhesin BAD1 is required for virulence of Blastomyces dermatitidis in a pulmonary model of infection. Herein, we explored mechanisms by which BAD1 enhances pathogenicity of the fungus. Isogenic strains with and without BAD1 exhibited similar phenotypic differences in virulence by pulmonary and intravenous routes of infection, indicating that BAD1 may exert virulence beyond adherence to respiratory lining cells. Non-adhesive mechanisms including maintenance of intrinsic resistance of yeast against phagocyte responses and products were excluded. A shift in the balance of type 1 and 2 cytokines and in the cellular profile of the inflammatory response after the first week of pulmonary infection was associated with BAD1. By the second week of infection, infection with wild-type yeast was associated with less IL-12 and IFN-gamma, and more IL-10, and an influx of inflammatory cells rich in neutrophils and poor in T-cells, when compared to infection with the BAD1 null strain. Taken together with previously reported BAD1 perturbations of TNF-gamma and TGF-beta, these data suggest that BAD1 contributes significantly to the pathogenicity of B. dermatitidis by also deviating host adaptive immunity, and leukocyte responses.
authors.affiliation: Department of Pediatrics, University of Wisconsin Medical School, University of Wisconsin Hospital and Clinics, Madison, WI 53792, USA. mwuethri@wisc.edu
authors.forename: Marcel
authors.initials: M
authors.lastname: Wüthrich
authors.forename: Beatriz
authors.initials: B
authors.lastname: Finkel-Jimenez
authors.forename: Tristan T
authors.initials: TT
authors.lastname: Brandhorst
authors.forename: Hanna I
authors.initials: HI
authors.lastname: Filutowicz
authors.forename: Tom
authors.initials: T
authors.lastname: Warner
authors.forename: Bruce S
authors.initials: BS
authors.lastname: Klein
mesh_terms: D000818:Animals; D001758:Blastomyces / Q000235:genetics / Q000472:pathogenicity*; D001759:Blastomycosis / Q000276:immunology / Q000382:microbiology*; D015169:Colony Count, Microbial; D004195:Disease Models, Animal; D005656:Fungal Proteins / Q000235:genetics / Q000502:physiology*; D017353:Gene Deletion; D006023:Glycoproteins / Q000235:genetics / Q000502:physiology*; D006651:Histocytochemistry; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis; D016753:Interleukin-10 / Q000096:biosynthesis; D018664:Interleukin-12 / Q000096:biosynthesis; D008168:Lung / Q000276:immunology / Q000473:pathology; D008172:Lung Diseases, Fungal / Q000276:immunology / Q000382:microbiology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009504:Neutrophils / Q000276:immunology; D037521:Virulence Factors / Q000235:genetics / Q000502:physiology*
chemical_list: D005656:Fungal Proteins; D006023:Glycoproteins; D037521:Virulence Factors; D016753:Interleukin-10; D018664:Interleukin-12; D007371:Interferon-gamma