Outer membrane protein size and LPS O-antigen define protective antibody targeting to the Salmonella surface

Dom�nguez-Medina, C. Coral; P�rez-Toledo, Marisol; Schager, Anna E.; Marshall, Jennifer L.; Cook, Charlotte N.; Bobat, Saeeda; Hwang, Hyea; Chun, Byeong Jae; Logan, Erin; Bryant, Jack A.; Channell, Will M.; Morris, Faye C.; Jossi, Sian E.; Alshayea, Areej; Rossiter, Amanda E.; Barrow, Paul A.; Horsnell, William G.; MacLennan, Calman A.; Henderson, Ian R.; Lakey, Jeremy H.; Gumbart, James C.; L�pez-Mac�as, Constantino; Bavro, Vassiliy N.; Cunningham, Adam F.

Abstract

Lipopolysaccharide (LPS) O-antigen (O-Ag) is known to limit antibody binding to surface antigens, although the relationship between antibody, O-Ag and other outer-membrane antigens is poorly understood. Here we report, immunization with the trimeric porin OmpD from Salmonella Typhimurium (STmOmpD) protects against infection. Atomistic molecular dynamics simulations indicate this is because OmpD trimers generate footprints within the O-Ag layer sufficiently sized for a single IgG Fab to access. While STmOmpD differs from its orthologue in S. Enteritidis (SEn) by a single amino-acid residue, immunization with STmOmpD confers minimal protection to SEn. This is due to the OmpD-O-Ag interplay restricting IgG binding, with the pairing of OmpD with its native O-Ag being essential for optimal protection after immunization. Thus, both the chemical and physical structure of O-Ag are key for the presentation of specific epitopes within proteinaceous surface-antigens. This enhances combinatorial antigenic diversity in Gram-negative bacteria, while reducing associated fitness costs.

Citation

Domínguez-Medina, C. C., Pérez-Toledo, M., Schager, A. E., Marshall, J. L., Cook, C. N., Bobat, S., …Cunningham, A. F. (2020). Outer membrane protein size and LPS O-antigen define protective antibody targeting to the Salmonella surface. Nature Communications, 11, Article 851. https://doi.org/10.1038/s41467-020-14655-9

• Journal Article Type: Article
• Acceptance Date: Jan 23, 2020
• Online Publication Date: Feb 12, 2020
• Publication Date: 2020-12
• Deposit Date: Nov 9, 2020
• Publicly Available Date: Nov 12, 2020
• Journal: Nature Communications
• Electronic ISSN: 2041-1723
• Publisher: Nature Publishing Group
• Peer Reviewed: Peer Reviewed
• Volume: 11
• Article Number: 851
• DOI: https://doi.org/10.1038/s41467-020-14655-9
• Keywords: General Biochemistry, Genetics and Molecular Biology; General Physics and Astronomy; General Chemistry
• Public URL: https://nottingham-repository.worktribe.com/output/4523587
• Publisher URL: https://www.nature.com/articles/s41467-020-14655-9
• Additional Information: Received: 5 March 2019; Accepted: 23 January 2020; First Online: 12 February 2020; : In 2008, Prof. Cunningham patented OmpD as a component of a vaccine against nontyphoidal Salmonella infections. The remaining authors declare no competing interests.