2024/06/11 by Robert Ernst, Robert K. Ernst, Matthew Sherman +14 · 1 voice
Biochemistry, Genetics and Molecular Biology · Immunology and Microbiology · #Cancer Research and Treatments #Escherichia coli research studies #Immune Response and Inflammation
paper · pdf · doi:10.21203/rs.3.rs-4448907/v1
crossref issued 2024/06/11 · crossref published 2024/06/11 · openalex publication_date 2024/06/11 · crossref created 2024/06/11 · crossref deposited 2024/06/11 · openalex created_date 2024/06/12 · crossref indexed 2025/05/14 · openalex updated_date 2026/08/01
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.