AUTHOR=Gonzales S. Jake , Clarke Kathleen N. , Batugedara Gayani , Garza Rolando , Braddom Ashley E. , Reyes Raphael A. , Ssewanyana Isaac , Garrison Kendra C. , Ippolito Gregory C. , Greenhouse Bryan , Bol Sebastiaan , Bunnik Evelien M. 

TITLE=A Molecular Analysis of Memory B Cell and Antibody Responses Against Plasmodium falciparum Merozoite Surface Protein 1 in Children and Adults From Uganda

JOURNAL=Frontiers in Immunology

VOLUME=13

YEAR=2022

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2022.809264

DOI=10.3389/fimmu.2022.809264

ISSN=1664-3224

ABSTRACT=<p>Memory B cells (MBCs) and plasma antibodies against <italic>Plasmodium falciparum</italic> (<italic>Pf</italic>) merozoite antigens are important components of the protective immune response against malaria. To gain understanding of how responses against <italic>Pf</italic> develop in these two arms of the humoral immune system, we evaluated MBC and antibody responses against the most abundant merozoite antigen, full-length <italic>Pf</italic> merozoite surface protein 1 (PfMSP1<sub>FL</sub>), in individuals from a region in Uganda with high <italic>Pf</italic> transmission. Our results showed that PfMSP1<sub>FL</sub>-specific B cells in adults with immunological protection against malaria were predominantly IgG<sup>+</sup> classical MBCs, while children with incomplete protection mainly harbored IgM<sup>+</sup> PfMSP1<sub>FL</sub>-specific classical MBCs. In contrast, anti-PfMSP1<sub>FL</sub> plasma IgM reactivity was minimal in both children and adults. Instead, both groups showed high plasma IgG reactivity against PfMSP1<sub>FL</sub>, with broadening of the response against non-3D7 strains in adults. The B cell receptors encoded by PfMSP1<sub>FL</sub>-specific IgG<sup>+</sup> MBCs carried high levels of amino acid substitutions and recognized relatively conserved epitopes on the highly variable PfMSP1 protein. Proteomics analysis of PfMSP1<sub>19</sub>-specific IgG in plasma of an adult revealed a limited repertoire of anti-MSP1 antibodies, most of which were IgG<sub>1</sub> or IgG<sub>3</sub>. Similar to B cell receptors of PfMSP1<sub>FL</sub>-specific MBCs, anti-PfMSP1<sub>19</sub> IgGs had high levels of amino acid substitutions and their sequences were predominantly found in classical MBCs, not atypical MBCs. Collectively, these results showed evolution of the PfMSP1-specific humoral immune response with cumulative <italic>Pf</italic> exposure, with a shift from IgM<sup>+</sup> to IgG<sup>+</sup> B cell memory, diversification of B cells from germline, and stronger recognition of PfMSP1 variants by the plasma IgG repertoire.</p>