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A High-throughput Shigella-specific Bactericidal Assay
Published on: February 27, 2019
BECC-engineered live-attenuated Shigella vaccine candidates display reduced endotoxicity with robust immunogenicity
Matthew E Sherman1, Jane Michalski1,2, Sayan Das1
1University of Maryland-Baltimore, Department of Microbial Pathogenesis, Baltimore, MD 21201 USA.
Insights
Researchers engineered live-attenuated Shigella vaccines using bacterial enzymatic combinatorial chemistry (BECC). This modification reduced endotoxicity while maintaining immunogenicity, offering a promising path toward safer Shigella vaccines.
Area of Science:
- Microbiology
- Vaccinology
- Biotechnology
Background:
- Shigella infections cause significant global disease, particularly in children.
- Existing therapeutic options are limited due to increasing antibiotic resistance.
- Current Shigella vaccine candidates have inflammatory lipid A structures, causing endotoxicity.
Purpose of the Study:
- To engineer safer live-attenuated Shigella vaccine strains.
- To reduce the inflammatory properties of Shigella lipopolysaccharide (LPS).
- To assess the safety and immunogenicity of modified vaccine strains.
Main Methods:
- Utilized bacterial enzymatic combinatorial chemistry (BECC) to modify lipid A structures.
- Ectopically expressed lipid A modifying enzymes in Shigella strains.
- Assessed LPS-induced TLR4 signaling in vitro and endotoxic effects in vivo.
Main Results:
- Dephosphorylation of lipid A reduced LPS-induced TLR4 signaling and in vivo endotoxicity.
- BECC-modified strains retained parental invasion and immunogenicity traits.
- Engineered vaccines exhibited reduced adverse endotoxicity.
Conclusions:
- Bacterial enzymatic combinatorial chemistry (BECC) is effective for engineering safer Shigella vaccines.
- Targeted lipid A modification can mitigate LPS-induced inflammation.
- BECC-engineered live attenuated Shigella vaccines represent a promising approach for development.
Abstract:
Shigella spp. infection contributes significantly to the global disease burden, primarily affecting young children in developing countries. Currently, there are no FDA-approved vaccines against Shigella, and the prevalence of antibiotic resistance is increasing, making therapeutic options limited. Live-attenuated vaccine strains WRSs2 (S. sonnei) and WRSf2G12 (S. flexneri 2a) are highly immunogenic, making them promising vaccine candidates, but possess an inflammatory lipid A structure on their lipopolysaccharide (LPS; also known as endotoxin). Here, we utilized bacterial enzymatic combinatorial chemistry (BECC) to ectopically express lipid A modifying enzymes in WRSs2 and WRSf2G12, as well as their respective wild-type strains, generating targeted lipid A modifications across the Shigella backgrounds. Dephosphorylation of lipid A, rather than deacylation, reduced LPS-induced TLR4 signaling in vitro and dampened endotoxic effects in vivo. These BECC-modified vaccine strains retained the phenotypic traits of their parental strains, such as invasion of epithelial cells and immunogenicity in mice without adverse endotoxicity. Overall, our observations suggest that BECC-engineered live attenuated vaccines are a promising approach to safe and effective Shigella vaccines.
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