AUTHOR=Richardson Nicole I. , Kuttel Michelle M. , Ravenscroft Neil 

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

JOURNAL=Frontiers in Molecular Biosciences

VOLUME=9

YEAR=2022

URL=https://www.frontiersin.org/journals/molecular-biosciences/articles/10.3389/fmolb.2022.961532

DOI=10.3389/fmolb.2022.961532

ISSN=2296-889X

ABSTRACT=<p><italic>Streptococcus pneumoniae</italic> is an encapsulated gram-negative bacterium and a significant human pathogen<italic>.</italic> 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, <italic>S. pneumoniae</italic> 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 <inline-formula id="inf1"><mml:math id="m1" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mi>β</mml:mi></mml:math></inline-formula>-D-galactofuranose (<inline-formula id="inf2"><mml:math id="m2" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mi>β</mml:mi></mml:math></inline-formula> DGal<italic>f</italic>) side chains that are potential antibody binding sites. We identify four distinct conformational epitopes for the immunodominant <inline-formula id="inf3"><mml:math id="m3" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mi>β</mml:mi></mml:math></inline-formula> DGal<italic>f</italic> 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 <inline-formula id="inf4"><mml:math id="m4" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mi>β</mml:mi></mml:math></inline-formula> DGal<italic>f</italic> in each serotype; the relative accessibility of three- or six-linked <inline-formula id="inf5"><mml:math id="m5" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mi>β</mml:mi></mml:math></inline-formula> DGal<italic>f</italic> 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.</p>