Mannoprotein Cig1 contributes to the immunogenicity of a heat-killed F-box protein Fbp1 Cryptococcus neoformans
Samantha L Avina1,2, Siddhi Pawar1,2, Roshni N Kadam1,2
1School of Graduate Studies at the Health Science Campus, New Jersey Medical School, Rutgers University Newark, Newark, New Jersey, USA.
Abstract:
Currently, no fungal vaccine exists for clinical use, while fungal infections are responsible for over 1.5 million deaths every year. Our previous studies identified a Cryptococcus neoformans mutant strain fbp1Δ as a potential vaccine candidate. This strain contains deletion of the F-box protein Fbp1, a key subunit of the SCF E3 ligase complex necessary for ubiquitin-mediated proteolysis. Vaccination with heat-killed fbp1Δ (HK-fbp1) can elicit an interferon gamma (IFN-γ)-dependent Type 1 immune response and provide protection against C. neoformans and its sibling species C. gattii. However, we have yet to decipher the immunogenic factor(s) expressed by the fbp1∆ mutant that are responsible for the induction of the protective immune response. In this study, we have identified that the capsule plays an important role in HK-fbp1 vaccine-mediated protection as acapsular HK-fbp1 cells showed diminished protection against wild-type challenge. Additionally, our studies have shown that Cytokine Inducing Glycoprotein 1 (Cig1), a GPI-anchored mannoprotein, is regulated by Fbp1 and contributes to the immunogenicity of HK-fbp1. Deletion of Cig1 in the fbp1Δ background resulted in decreased recruitment of antifungal effector T cells and diminished production of protective inflammatory cytokines by the host. Furthermore, loss of Cig1 in the fbp1Δ mutant resulted in reduced protection in vaccination survival studies at lower vaccine inoculum doses compared to HK-fbp1. In aggregate, these findings demonstrate Cig1 is an antigen contributing to the immunogenicity of HK-fbp1 that may be utilized to further optimize the HK-fbp1 fungal vaccine as a tool in the arsenal against invasive fungal infections.
Insights
The heat-killed *Cryptococcus neoformans* fbp1Δ mutant vaccine shows promise, with Cig1 identified as a key antigen enhancing protection against fungal infections by boosting immune responses.
Area of Science:
- Mycology
- Immunology
- Vaccinology
Background:
- Fungal infections cause over 1.5 million deaths annually, with no existing clinical fungal vaccine.
- A *Cryptococcus neoformans* mutant strain, *fbp1*Δ, has shown potential as a vaccine candidate, inducing an interferon gamma (IFN-γ)-dependent immune response.
- The specific immunogenic factors responsible for the protective effects of the heat-killed *fbp1*Δ (HK-*fbp1*) vaccine remain unidentified.
Purpose of the Study:
- To identify the immunogenic factors in the HK-*fbp1* vaccine responsible for protective immunity against fungal infections.
- To investigate the role of the fungal capsule and Cytokine Inducing Glycoprotein 1 (Cig1) in the efficacy of the HK-*fbp1* vaccine.
Main Methods:
- Comparative analysis of acapsular HK-*fbp1* cells versus encapsulated cells in protection studies.
- Genetic manipulation of the *fbp1*Δ mutant to assess the impact of Cig1 deletion on vaccine efficacy.
- Evaluation of immune responses, including T cell recruitment and cytokine production, in vaccinated hosts challenged with *C. neoformans*.
Main Results:
- Acapsular HK-*fbp1* cells demonstrated diminished protection against wild-type fungal challenge, highlighting the capsule's importance.
- Cytokine Inducing Glycoprotein 1 (Cig1), regulated by Fbp1, was identified as a significant contributor to HK-*fbp1* immunogenicity.
- Deletion of Cig1 in the *fbp1*Δ mutant led to reduced antifungal T cell recruitment, lower protective cytokine levels, and decreased survival rates at lower vaccine doses.
Conclusions:
- The fungal capsule and Cig1 are critical components contributing to the protective efficacy of the HK-*fbp1* vaccine.
- Cig1 is a key antigen that enhances the immunogenicity of the HK-*fbp1* vaccine.
- Further optimization of the HK-*fbp1* vaccine by leveraging Cig1 could provide a valuable tool against invasive fungal infections.
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