Modeling of pneumococcal serogroup 10 capsular polysaccharide molecular conformations provides insight into epitopes and observed cross-reactivity.

Richardson, N. I. and Kuttel, M. M. and Ravenscroft, N. (2022) Modeling of pneumococcal serogroup 10 capsular polysaccharide molecular conformations provides insight into epitopes and observed cross-reactivity., Front. Mol. Biosci., 9, Frontiers.

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Abstract

Streptococcus pneumoniae is an encapsulated gram-negative bacterium and a significant human pathogen. The capsular polysaccharide (CPS) is essential for virulence and a target antigen for vaccines. Although widespread introduction of pneumococcal conjugate vaccines (PCVs) has significantly reduced disease, the prevalence of non-vaccine serotypes has increased. On the basis of the CPS, S. pneumoniae serogroup 10 comprises four main serotypes 10A, 10B, 10C, and 10F; as well as the recently identified 10D. As it is the most prevalent, serotype 10A CPS has been included as a vaccine antigen in the next generation PCVs. Here we use molecular modeling to provide conformational rationales for the complex cross-reactivity reported between serotypes 10A, 10B, 10C, and 10F anti-sera. Although the highly mobile phosphodiester linkages produce very flexible CPS, shorter segments are conformationally defined, with exposed β-D-galactofuranose (β DGalf) side chains that are potential antibody binding sites. We identify four distinct conformational epitopes for the immunodominant β DGalf that assist in rationalizing the complex asymmetric cross-reactivity relationships. In particular, we find that strongly cross-reactive serotypes share common epitopes. Further, we show that human intelectin-1 has the potential to bind the exposed exocyclic 1,2-diol of the terminal β DGalf in each serotype; the relative accessibility of three- or six-linked β DGalf may play a role in the strength of the innate immune response and hence serotype disease prevalence. In conclusion, our modeling study and relevant serological studies support the inclusion of serotype 10A in a vaccine to best protect against serogroup 10 disease.

Item Type:	Journal article (online only)
Additional Information:	DOI: 10.3389/fmolb.2022.961532
Subjects:	Computing methodologies > Modeling and simulation > Simulation types and techniques > Molecular simulation Applied computing > Physical sciences and engineering > Chemistry
Date Deposited:	17 Sep 2022 08:54
Last Modified:	17 Sep 2022 08:54
URI:	https://pubs.cs.uct.ac.za/id/eprint/1538

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