B cell receptor repertoire analysis in malaria-naive and malaria-experienced individuals reveals unique characteristics of atypical memory b cells

Malaria, caused by parasites of the Plasmodium genus, is responsible for significant morbidity and mortality globally. Chronic Plasmodium falciparum exposure affects the B cell compartment, leading to the accumulation of atypical memory B cells (atMBCs). IgM-positive (IgM1) and IgG1 atMBCs have not been compared in-depth in the context of malaria, nor is it known if atMBCs in malaria-experienced individuals are different from phenotypically similar B cells in individuals with no known history of Plasmodium exposure. To address these questions, we characterized the B cell receptor (BCR) repertoire of naive B cells (NBCs), IgM1 and IgG1 classical MBCs (cMBCs), and IgM1 and IgG1 atMBCs from 13 malaria-naive American adults and 7 malaria-experienced Ugandan adults. Our results demonstrate that P. falciparum exposure mainly drives changes in atMBCs. In comparison to malaria-naive adults, the BCR repertoire of Plasmodium-exposed adults showed increased levels of somatic hypermutation in the heavy chain V region in IgM1 and IgG1 atMBCs, shorter heavy chain complementaritydetermining region 3 (HCDR3) in IgG1 atMBCs, and increased usage of IGHV3-73 in IgG1 cMBCs and both IgM1 and IgG1 atMBCs. Irrespective of Plasmodium exposure, IgM1 atMBCs closely resembled NBCs, while IgG1 atMBCs resembled IgG1 cMBCs. Physicochemical properties of the HCDR3 seemed to be intrinsic to cell type and independent of malaria experience. The resemblance between atMBCs from Plasmodium-exposed and naive adults suggests similar differentiation pathways regardless of chronic antigen exposure. Moreover, these data demonstrate that IgM1 and IgG1 atMBCs are distinct populations that should be considered separately in future analyses.