title: Immunological basis for susceptibility and resistance to pulmonary blastomycosis in mouse strains.
abstract: The immunological basis for a >10-fold resistance of outbred CD-1 mice compared to inbred BALB/c mice to pulmonary blastomycosis was investigated. Bronchoalveolar macrophages (BAM) from CD-1 mice killed yeast cells of Blastomyces dermatitidis (Bd) by 25% and this increased to 59% when activated by IFN-gamma. In contrast, BAM from BALB/c mice lacked significant killing (5%) of Bd but could be activated by IFN-gamma for enhanced killing (19%). Peritoneal macrophages (PM) from CD-1 mice had significant fungicidal activity for Bd (43%) and this increased to 63% with IFN-gamma treatment. By contrast, PM from BALB/c mice did not significantly kill Bd (14%) but were activated by IFN-gamma for significant killing (24%). Fungicidal activity of peripheral blood polymorphonuclear neutrophils (PMN) from CD-1 (87%) was greater than that of BALB/c (75%) (P<0.05). Macrophage inflammatory protein-1alpha (MIP-1alpha) production by BAM from BALB/c was significantly less than that from CD-1 in response to co-culture with Bd. IFN-gamma production by CD-1 spleen cells in response to concanavalin A (Con A, 1microg/ml) was 8-fold greater than that by BALB/c spleen cells. In contrast, BAM and PM from BALB/c mice in co-culture with Bd secreted several-fold more TNFalpha than BAM or PM from CD-1 mice. IL-2 production by BALB/c spleen cells in response to Con A was 3- to 4-fold greater than that by CD-1 spleen cells. Depressed IL-2 production by Con A stimulated CD-1 spleen cells correlated with depressed proliferative responses. Resistance of CD-1 mice to pulmonary blastomycosis correlates with enhanced fungicidal activity of BAM, PM, PMN, and IFN-gamma production by Con A stimulated spleen cells, compared to BALB/c mice. Consistent with the in vitro enhancement of effector cell function by IFN-gamma, in vivo therapy with IFN-gamma significantly (P<0.0001) improved survival of BALB/c mice with pulmonary blastomycosis.
authors.affiliation: Division of Infectious Diseases, Department of Medicine, Santa Clara Valley Medical Center, San Jose, CA 95128-2699, USA. e.brummer@juno.com
authors.forename: Elmer
authors.initials: E
authors.lastname: Brummer
authors.forename: Neelima
authors.initials: N
authors.lastname: Kethineni
authors.forename: David A
authors.initials: DA
authors.lastname: Stevens
mesh_terms: D000818:Animals; D001759:Blastomycosis / Q000276:immunology* / Q000378:metabolism / Q000401:mortality; D049109:Cell Proliferation; D002478:Cells, Cultured; D018920:Coculture Techniques; D004198:Disease Susceptibility / Q000276:immunology; D007113:Immunity, Innate; D008172:Lung Diseases, Fungal / Q000276:immunology* / Q000378:metabolism / Q000401:mortality; D019402:Macrophage Inflammatory Proteins / Q000096:biosynthesis; D016676:Macrophages, Alveolar / Q000378:metabolism; D017737:Macrophages, Peritoneal / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009504:Neutrophils / Q000378:metabolism; D009569:Nitric Oxide / Q000096:biosynthesis; D013154:Spleen / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D019402:Macrophage Inflammatory Proteins; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide