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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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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Adoptive transfer of DTH and resistance to B. dermatitidis by immune spl...
Adoptive transfer of DTH and resistance to B. dermatitidis by immune splenocytes and lymph node cells. Mice were immunized three times subcutaneously with strain no. 55, and 2 weeks later, boosted with CW/M or YSP antigen in CFA. As a control, mice were immunized three times with hen egg lysozyme (HEL) in Freund’s. Ten days after immunization, cells were harvested and passively transferred into naive mice. (a) DTH. Two hours after transfer, two mice per group were injected with 105 heat-killed yeast of strain no. 55 into one hind footpad and PBS into the other. Footpad swelling is depicted as mean ± SEM. (b) Burden of lung infection. One day after transfer, groups of 10 mice were infected intratracheally with 2 × 102 yeast of wild-type strain 26199; they were analyzed for lung CFU 3 weeks later. P values are in comparison to corresponding lymphoid populations of HEL controls.