The WI-1 Adhesin Blocks Phagocyte TNF-#alpha# Production, Imparting Pathogenicity on Blastomyces dermatitidis

摘要

The WI-1 adhesin is indispensable for pathogenicity of Blastomyces dermatitidis and is thought to promote pulmonary infection fixing yeast to lung tissue and cells. Recent findings suggest that WI-1 confers pathogenicity by mechanisms in addition adherence. Here, we investigated whether WI-1 modulates host immunity by altering production of pro-inOammatory cytokinl Production of TNF-a in lung alveolar Ouids of mice infected with B. dermatitidis was severalfold higher for WI-1 knockout ye~ compared with wild-type yeast, and in vitro coculture of unseparated lung cells with these isogenic yeast disclosed similar d ferences. Upon coculture with purified macrophages and neutrophils, wild-type yeast blocked TNF~a production, yet WI-1 knoc out yeast stimulated production. Coating knockout yeast with purified WI-1 converted them from stimulating TNF-a productil to inhibiting production. Addition of purified WI-1 into stimulated phagocyte cultures led to concentration-dependent inhibitil of TNF -a production. Neutralization of TNF -a in vivo exacerbated experimental pulmonary infection, particularly for the no pathogeuic WI-1 knockout yeast. Inducing increased TNF-a levels in the lung by adenovirus-vectored gene therapy controll infection with wild-type yeast. Thus, the WI-1 adhesin on yeast modulates host immunity through blocking TNF-a production phagocytes, which fosters progression of pulmonary infection.