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Whole glucan particles as a vaccine against murine aspergillosis
Karl V Clemons1,2,3, Michael E Danielson4, Kyle S Michel4
1Division of Infectious Diseases and Geographic Medicine, Stanford University, Stanford, CA, USA.
Abstract:
Vaccination with heat-killed Saccharomyces cerevisiae (HKY) protects against experimental infection by pathogenic fungi of five genera. Here we tested whether purified Saccharomyces cell wall β-glucan could induce protection against systemic aspergillosis. CD-1 mice were given three weekly vaccine doses subcutaneously prior to intravenous infection with Aspergillus fumigatus. Mice received PBS, 2.5 mg HKY, whole glucan particles (WGP), WGP conjugated to BSA (0.06 to 12 mg per dose), a soluble medium molecular mass (MMW) β-glucan alone or MMW-BSA (≤24 mg per dose). Survival and c.f.u. were determined, and cytokine induction and anti-β-glucan antibodies were assessed in vaccinated mice. Neither soluble MMW glucan, nor MMW-BSA was effective. HKY protected in two studies (survival and c.f.u. were reduced in brain and kidney organs, P<0.004). Six or 12 mg WGP or WGP-BSA prolonged survival (P≤0.004) and reduced c.f.u. in each organ (P≤0.015) in both experiments; 0.6 mg WGP or WGP-BSA prolonged survival (P≤0.015) and reduced c.f.u. (P≤0.015) in one experiment. Cytokine profiles in serum and bronchoalveolar lavage from uninfected vaccinated mice showed an innate and adaptive immune profile (i.e. upregulation of colony stimulating factors, interferons, TNF-α, chemokines such as MCP-1, MIP-1α, RANTES and KC, and Th17-activating cytokines such as IL-6, IL-1β, IL-17). No anti-β-glucan antibodies were in the sera, suggesting an adaptive T cell-mediated, not a B cell-mediated, protective response. Vaccination with WGP or WGP-BSA proved protective against systemic aspergillosis, equivalent to that of HKY, supporting the potential of particulate β-glucans, alone or conjugated, as vaccines against aspergillosis.
Insights
Particulate β-glucans from Saccharomyces, including whole glucan particles (WGP) and WGP-BSA, effectively protect against systemic aspergillosis in mice. This immune response appears T cell-mediated, not B cell-mediated.
Area of Science:
- Immunology
- Mycology
- Vaccinology
Background:
- Heat-killed Saccharomyces cerevisiae (HKY) vaccination confers protection against fungal infections.
- Systemic aspergillosis, caused by Aspergillus fumigatus, remains a significant clinical challenge.
- The immunomodulatory properties of fungal β-glucans are well-established.
Purpose of the Study:
- To evaluate the efficacy of purified Saccharomyces cell wall β-glucan in protecting against systemic aspergillosis.
- To compare the protective potential of particulate β-glucans (WGP, WGP-BSA) with soluble β-glucans and HKY.
- To elucidate the immune mechanisms underlying β-glucan-induced protection.
Main Methods:
- CD-1 mice were vaccinated subcutaneously with various β-glucan preparations (HKY, WGP, WGP-BSA, soluble MMW β-glucan, MMW-BSA) prior to intravenous Aspergillus fumigatus infection.
- Survival rates and fungal colony-forming units (c.f.u.) in organs were assessed.
- Cytokine profiles and anti-β-glucan antibodies were analyzed in vaccinated, uninfected mice.
Main Results:
- Particulate β-glucans (WGP and WGP-BSA) significantly prolonged survival and reduced fungal burden in mice infected with Aspergillus fumigatus.
- Soluble β-glucan preparations (MMW glucan, MMW-BSA) did not confer protection.
- Vaccination induced a mixed innate and adaptive immune response, characterized by upregulation of pro-inflammatory cytokines and chemokines, with no detectable anti-β-glucan antibodies, suggesting T cell involvement.
Conclusions:
- Particulate β-glucans, including whole glucan particles (WGP) and their conjugates (WGP-BSA), are effective vaccines against systemic aspergillosis in a murine model.
- The protective immunity elicited by particulate β-glucans is comparable to that of heat-killed Saccharomyces cerevisiae (HKY).
- These findings support the development of particulate β-glucans as potential vaccine candidates for preventing aspergillosis.
