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BAD1, an Essential Virulence Factor of Blastomyces dermatitidis, Suppresses Host TNF- Production Through TGF--Dependent and -Independent Mechanisms¹

Beatriz Finkel-Jimenez^*, Marcel Wüthrich^* and Bruce S. Klein^2,*,,,

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

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- production in response to the fungus; isogenic, attenuated BAD1 knockout yeast did not have this effect. Phagocytes released 4- to 5-fold more TGF- in vitro in response to wild-type yeast vs BAD1 knockout yeast. Treatment of inhibitory, conditioned supernatant with anti-TGF- mAb neutralized detectable TGF- and restored phagocyte TNF- production. Similarly, addition of anti-TGF- mAb into cultures of phagocytes and wild-type yeast reversed BAD1 inhibition of TNF- production. Conversely, TGF- treatment of phagocytes cultured with knockout yeast suppressed TNF- production. Hence, TGF- mediates BAD1 suppression of TNF- by wild-type B. dermatitidis cultured in vitro with phagocytes. In contrast to these findings, neutralization of elevated TGF- levels during experimental pulmonary blastomycosis did not restore BAD1-suppressed TNF- levels in the lung or ameliorate disease. Soluble BAD1 was found to accumulate in the alveoli of infected mice at levels that suppressed TNF- production by phagocytes. However, in contrast to yeast cell surface BAD1, which induced TGF-, soluble BAD1 failed to do so and TNF- suppression mediated by soluble BAD1 was unaffected by neutralization of TGF-. Thus, BAD1 of B. dermatitidis induces suppression of TNF- and progressive infection by both TGF--dependent and -independent mechanisms.

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