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Characterization of dual DNA polymerase knockout strains of Candida albicans with live whole-cell vaccine competence
Abinash Dutta1, Satya Ranjan Sahu1,2, Bhabasha Gyanadeep Utkalaja1,2
1Department of Infectious Disease Biology, Institute of Life Sciences, Bhubaneswar, India.
Abstract:
Systemic candidiasis inflicts ~1.2 million deaths annually worldwide. Despite its severity, an approved antifungal vaccine remains an unmet human need. In a quest to design a live-whole cell vaccine, we characterized and demonstrated the vaccine potential of two dual DNA polymerase-defective strains of Candida albicans. While the deletion of POL32 in a hyper-virulent rad30ΔΔ strain attenuated the virulence, the deletion of RAD30 in an avirulent pol32ΔΔ did not revert to a hypervirulence phenotype. Both the dual polymerase-defective strains replicate transiently in the host and trigger immune responses to prevent reinfections in mice by employing a concerted involvement of innate, adaptive, and trained immunity. The cellular and molecular depletion in immunized mice suggested the role of B- and T-cells, neutrophils, and macrophages in antifungal immunity. Altogether, our results confirmed that Pol32 is a true virulence factor and intravenous vaccination with these attenuated strains could prevent systemic candidiasis in the preclinical models without evident safety concerns; thus, these candidate strains have enormous translational potential to fully develop as antifungal vaccines.
Insights
Developing a novel antifungal vaccine, researchers created dual DNA polymerase-defective Candida albicans strains. These attenuated strains successfully prevented systemic candidiasis in mice by stimulating robust immune responses.
Area of Science:
- Mycology
- Immunology
- Vaccine Development
Background:
- Systemic candidiasis causes over a million deaths annually, highlighting the urgent need for effective antifungal vaccines.
- Current therapeutic options for invasive fungal infections are limited, necessitating innovative preventative strategies.
Purpose of the Study:
- To investigate the vaccine potential of dual DNA polymerase-defective Candida albicans strains.
- To evaluate the safety and efficacy of these attenuated strains in preventing systemic candidiasis.
Main Methods:
- Characterization of two dual DNA polymerase-defective Candida albicans strains (rad30ΔΔ pol32ΔΔ).
- Assessment of strain virulence and immunogenicity in preclinical mouse models.
- Analysis of immune cell involvement (B-cells, T-cells, neutrophils, macrophages) in vaccine-induced protection.
Main Results:
- Deletion of POL32 attenuated virulence in a hyper-virulent strain, while RAD30 deletion did not revert avirulence.
- Both dual-defective strains replicated transiently, inducing innate, adaptive, and trained immunity.
- Vaccination prevented systemic candidiasis in mice without apparent safety concerns, implicating key immune cells.
Conclusions:
- Pol32 is identified as a significant virulence factor in Candida albicans.
- Intravenous administration of these attenuated strains shows promise as a live-whole cell antifungal vaccine.
- The candidate strains possess substantial translational potential for developing a much-needed vaccine against systemic candidiasis.
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