The WI-1 adhesin blocks phagocyte TNP-alpha production, imparting pathogenicity on Blastomyces dermatitidis

The WI-1 adhesin is indispensable for pathogenicity of Blastomyces dermatit idis and is thought to promote pulmonary infection by fixing yeast to lung tissue and cells. Recent findings suggest that WI-1 confers pathogenicity b y mechanisms in addition to adherence. Here, we investigated whether WI-1 m odulates 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 w ild-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-l knockout yeast stimulated production. Coating knockout yeast with purified WI-1 converted them from stimulating TNF-gamma production to inhi biting production. Addition of purified WI-I into stimulated phagocyte cult ures led to concentration-dependent inhibition of TNF-alpha production. Neu tralization of TNF-alpha in vivo exacerbated experimental pulmonary infecti on, particularly for the nonpathogenic WI-1 knockout yeast. Inducing increa sed TNF-alpha levels in the lung by adenovirus-vectored gene therapy contro lled infection with wild-type yeast. Thus, the WI-1 adhesin on yeast modula tes host immunity through blocking TNF-a production by phagocytes, which fo sters progression of pulmonary infection.