Mutation of the WI-1 gene yields an attenuated Blastomyces dermatitidis strain that induces host resistance
Marcel Wüthrich, … , Hanna I. Filutowicz, Bruce S. Klein
Marcel Wüthrich, … , Hanna I. Filutowicz, Bruce S. Klein
Published December 1, 2000
Citation Information: J Clin Invest. 2000;106(11):1381-1389. https://doi.org/10.1172/JCI11037.
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Article

Mutation of the WI-1 gene yields an attenuated Blastomyces dermatitidis strain that induces host resistance

Abstract

Systemic fungal infections are becoming more common and difficult to treat, and vaccine prevention is not available. Pulmonary infection with the dimorphic fungus Blastomyces dermatitidis often progresses and requires treatment to prevent fatality. We recently created a recombinant strain of the fungus lacking the WI-1 adhesin and pathogenicity. We show here that administration of viable yeast of this attenuated strain vaccinates against lethal pulmonary experimental infection due to isogenic and nonisogenic strains from diverse geographic regions. To our knowledge, this is the first example of a recombinant attenuated vaccine against fungi. The vaccine induces delayed-type hypersensitivity and polarized type 1 cytokine responses, which are linked with resistance. A cell-wall/membrane (CW/M) antigen from the vaccine strain also induces polarized and protective immune responses. Lymph node cells and CD4+ T-cell lines raised with CW/M antigen transfer protective immunity when they release type 1 cytokine IFN-γ, but not when they release IL-4, and neutralization of IFN-γ confirmed its role in vivo. Thus, by mutating a pathogenetic locus in a dimorphic fungus, we have created an attenuated vaccine strain and have begun to elucidate fungal and host elements requisite for vaccine immunity.

Authors

Marcel Wüthrich, Hanna I. Filutowicz, Bruce S. Klein

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Figure 1

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Acquired resistance to blastomycosis after vaccination with a recombinan...
Acquired resistance to blastomycosis after vaccination with a recombinant, live, attenuated strain of B. dermatitidis. (a) DTH responses. C57BL/6 mice were vaccinated by different routes: intranasal (i.n.), subcutaneous (s.c.), and intravenous (i.v.). After immunization, groups of four mice were injected with 105 dead yeast of strain no. 55 into one footpad or PBS into the other. Footpad swelling was measured 24 hours later. Error bars are SEM. (b) Burden of lung infection. Two weeks after immunization, groups of 10 mice were infected intranasally with 104 26199 wild-type yeast. Three weeks later, mice were analyzed for lung CFU. Geometric means of CFUs were calculated. Error bars are SEM. P values are for comparison of each immunized group versus nonimmune controls. (c) Survival after infection. Groups of ten C57BL/6 mice were infected as in b and monitored for survival over 128 days. P values are for comparison of each immunized group versus nonimmune mice.