BAD1, an essential virulence factor of Blastomyces dermatitidis, suppresses host TNF-alpha production through TGF-beta-dependent and -independent mechanisms.
We investigated how BAD1, an adhesin and virulence factor of Blastomyces dermatitidis, suppresses phagocyte proinflammatory responses. Wild-type yeast cocultured with murine neutrophils or macrophages prompted release of a soluble factor into conditioned supernatant that abolished TNF-alpha production in response to the fungus; isogenic, attenuated BAD1 knockout yeast did not have this effect. Phagocytes released 4- to 5-fold more TGF-beta in vitro in response to wild-type yeast vs BAD1 knockout yeast. Treatment of inhibitory, conditioned supernatant with anti-TGF-beta mAb neutralized detectable TGF-beta and restored phagocyte TNF-alpha production. Similarly, addition of anti-TGF-beta mAb into cultures of phagocytes and wild-type yeast reversed BAD1 inhibition of TNF-alpha production. Conversely, TGF-beta treatment of phagocytes cultured with knockout yeast suppressed TNF-alpha production. Hence, TGF-beta mediates BAD1 suppression of TNF-alpha by wild-type B. dermatitidis cultured in vitro with phagocytes. In contrast to these findings, neutralization of elevated TGF-beta levels during experimental pulmonary blastomycosis did not restore BAD1-suppressed TNF-alpha levels in the lung or ameliorate disease. Soluble BAD1 was found to accumulate in the alveoli of infected mice at levels that suppressed TNF-alpha production by phagocytes. However, in contrast to yeast cell surface BAD1, which induced TGF-beta, soluble BAD1 failed to do so and TNF-alpha suppression mediated by soluble BAD1 was unaffected by neutralization of TGF-beta. Thus, BAD1 of B. dermatitidis induces suppression of TNF-alpha and progressive infection by both TGF-beta-dependent and -independent mechanisms.
Finkel-Jimenez
Beatriz
B
Departments of. Pediatrics, Internal Medicine, and Medical Microbiology and Immunology, and Comprehensive Cancer Center, University of Wisconsin Medical School, University of Wisconsin Hospital and Clinics, Madison, WI 53792.
Wüthrich
Marcel
M
Klein
Bruce S
BS
D000818:Animals; D001758:Blastomyces / Q000472:pathogenicity*; D005656:Fungal Proteins; D006023:Glycoproteins / Q000633:toxicity*; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D016212:Transforming Growth Factor beta / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*
D005656:Fungal Proteins; D006023:Glycoproteins; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha