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Published on: August 8, 2017
Mutation of the WI-1 gene yields an attenuated blastomyces dermatitidis strain that induces host resistance
M Wüthrich1, H I Filutowicz, B S Klein
1Department of Pediatrics, The Comprehensive Cancer Center, University of Wisconsin Medical School, University of Wisconsin Hospital, Madison, USA.
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-gamma, but not when they release IL-4, and neutralization of IFN-gamma 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.
Insights
A novel recombinant attenuated vaccine using a weakened Blastomyces dermatitidis fungus strain shows promise for preventing lethal pulmonary fungal infections. This breakthrough offers a potential new strategy against challenging systemic fungal diseases.
Area of Science:
- Mycology
- Immunology
- Vaccinology
Background:
- Systemic fungal infections are increasing and difficult to treat, with no vaccines currently available.
- Pulmonary Blastomyces dermatitidis infections can be fatal and require effective treatment.
- Development of a vaccine against fungal pathogens is a critical unmet medical need.
Purpose of the Study:
- To evaluate a novel recombinant attenuated Blastomyces dermatitidis strain as a vaccine against experimental pulmonary infection.
- To investigate the immune mechanisms underlying the protective effects of the experimental vaccine.
- To explore the potential of cell-wall/membrane (CW/M) antigens from the vaccine strain in inducing protective immunity.
Main Methods:
- Creation of a recombinant Blastomyces dermatitidis strain lacking the WI-1 adhesin and pathogenicity.
- Administration of the viable attenuated yeast strain to experimental models to assess vaccination efficacy.
- Analysis of immune responses, including delayed-type hypersensitivity and cytokine profiles (IFN-gamma, IL-4).
- Evaluation of cell-wall/membrane (CW/M) antigens and their role in T-cell mediated immunity and protection.
Main Results:
- The attenuated recombinant strain successfully vaccinated against lethal pulmonary infection from various Blastomyces dermatitidis strains.
- The vaccine induced delayed-type hypersensitivity and type 1 polarized immune responses, correlated with resistance.
- A cell-wall/membrane (CW/M) antigen from the vaccine strain also elicited protective immune responses.
- Immunity was transferable via lymph node cells and CD4(+) T-cell lines releasing IFN-gamma, highlighting its crucial role in vivo.
Conclusions:
- A recombinant attenuated Blastomyces dermatitidis vaccine is effective in preventing experimental pulmonary fungal infections.
- Type 1 immune responses, particularly mediated by IFN-gamma, are essential for vaccine-induced protection.
- This study presents the first recombinant attenuated vaccine against a fungal pathogen and elucidates key immune correlates of protection.
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