Targeted gene disruption reveals an adhesin indispensable for pathogenicity of Blastomyces dermatitidis

Systemic fungal infections are becoming more common and difficult to treat, yet the pathogenesis of these infectious diseases remains poorly understoo d. In many cases, pathogenicity can be attributed to the ability of the fun gi to adhere to target tissues, but the lack of tractable genetic systems h as limited progress in understanding and interfering with the offending fun gal products. In Blastomyces dermatitidis, the agent of blastomycosis, a re spiratory and disseminated mycosis of people and animals worldwide, express ion of the putative adhesin encoded by the WI-1 gene was investigated as a possible virulence factor. DNA-mediated gene transfer was used to disrupt t he WI-1 locus by allelic replacement, resulting in impaired binding and ent ry of yeasts into macrophages, loss of adherence to lung tissue, and abolis hment of virulence in mice; each of these properties was fully restored aft er reconstitution of WI-1 by means of gene transfer. These findings establi sh the pivotal role of WI-1 in adherence and virulence of B. dermatitidis y easts. To our knowledge, they offer the first example of a genetically prov en virulence determinant among systemic dimorphic fungi, and underscore the value of reverse genetics for studies of pathogenesis in these organisms.