Blastomyces dermatitidis Yeast Cells Inhibit Nitric Oxide Production by Alveolar Macrophage Inducible Nitric Oxide Synthase

Abstract

ABSTRACTThe ability of pathogens to evade host antimicrobial mechanisms is crucial to their virulence. The dimorphic fungal pathogenBlastomyces dermatitidiscan infect immunocompetent patients, producing a primary pulmonary infection that can later disseminate to other organs.B. dermatitidispossesses a remarkable ability to resist killing by alveolar macrophages. To date, no mechanism to explain this resistance has been described. Here, we focus on macrophage production of the toxic molecule nitric oxide as a potential target of subversion byB. dermatitidisyeast cells. We report thatB. dermatitidisyeast cells reduce nitric oxide levels in the supernatants of activated alveolar macrophages. This reduction is not due to detoxification of nitric oxide, but rather to suppression of macrophage nitric oxide production. We show thatB. dermatitidisyeast cells do not block upregulation of macrophage inducible nitric oxide synthase (iNOS) expression or limit iNOS access to its arginine substrate. Instead,B. dermatitidisyeast cells appear to inhibit iNOS enzymatic activity. Further investigation into the genetic basis of this potential virulence mechanism could lead to the identification of novel antifungal drug targets.