B Cell Receptor Repertoire Analysis in Malaria-Naive and Malaria-Experienced Individuals Reveals Unique Characteristics of Atypical Memory B Cells

Braddom, Ashley; Bol, Sebastiaan; Gonzales, S. Jake; Reyes, Raphael A.; Musinguzi, Kenneth; Nankya, Felistas; Ssewanyana, Isaac; Greenhouse, Bryan; Bunnik, Evelien M.

doi:10.1128/msphere.00726-21

Cited by 13 publications

(10 citation statements)

References 61 publications

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“…Concerning the origin and clonality of atBCs, BCR sequencing analysis provided evidence of comparable SHM rates and clonal relationships between Pf- specific atBCs, actBCs, and MBCs, suggesting that these subsets originate from common affinity–matured B cell precursors. This is consistent with previous studies of bulk B cell subsets in malaria-exposed individuals in Mali ( 12 ), Kenya ( 10 ), and Uganda ( 39 ), but at odds with a study in Gabon that showed little evidence of clonal relationship between atBCs and MBCs ( 21 ).…”

Section: Discussionsupporting

confidence: 91%

Atypical B cells up-regulate costimulatory molecules during malaria and secrete antibodies with T follicular helper cell support

et al. 2022

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Several infectious and autoimmune diseases are associated with an expansion of CD21 − CD27 − atypical B cells (atBCs) that up-regulate inhibitory receptors and exhibit altered B cell receptor (BCR) signaling. The function of atBCs remains unclear, and few studies have investigated the biology of pathogen-specific atBCs during acute infection. Here, we performed longitudinal flow cytometry analyses and RNA sequencing of Plasmodium falciparum ( Pf )–specific B cells isolated from study participants before and shortly after febrile malaria, with simultaneous analysis of influenza hemagglutinin (HA)–specific B cells as a comparator. At the healthy baseline before the malaria season, individuals had similar frequencies of Pf - and HA-specific atBCs that did not differ proportionally from atBCs within the total B cell population. BCR sequencing identified clonal relationships between Pf -specific atBCs, activated B cells (actBCs), and classical memory B cells (MBCs) and revealed comparable degrees of somatic hypermutation. At the healthy baseline, Pf -specific atBCs were transcriptionally distinct from Pf -specific actBCs and classical MBCs. In response to acute febrile malaria, Pf -specific atBCs and actBCs up-regulated similar intracellular signaling cascades. Pf -specific atBCs showed activation of pathways involved in differentiation into antibody-secreting cells and up-regulation of molecules that mediate B-T cell interactions, suggesting that atBCs respond to T follicular helper (T FH ) cells. In the presence of T FH cells and staphylococcal enterotoxin B, atBCs of malaria-exposed individuals differentiated into CD38 + antibody-secreting cells in vitro, suggesting that atBCs may actively contribute to humoral immunity to infectious pathogens.

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Section: Discussionsupporting

confidence: 91%

Atypical B cells up-regulate costimulatory molecules during malaria and secrete antibodies with T follicular helper cell support

et al. 2022

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“…Although the results of this experiment will require confirmation in additional individuals, this is the first analysis of its kind in a malaria-experienced person and will provide valuable insight into the molecular characteristics of the anti-PfMSP1 plasma antibody repertoire after life-long exposure to Pf . In a previous study, we generated B cell receptor sequencing (BCR-seq) data of antibody heavy chain variable regions of naïve B cells, classical MBCs, and atypical MBCs ( 43 ). The full BCR-seq data set and all sequences obtained from PfMSP1-specific MBCs were used to construct a personalized, donor-specific reference heavy chain antibody variable region sequence database.…”

Section: Resultsmentioning

confidence: 99%

“…cycle time. B cell receptor sequencing data was available from a previous study ( 43 ). Demultiplexing of sequence reads and the generation of consensus sequences for UMI groups were performed as outlined by Turchaninova et al using software tools MIGEC (v1.2.9) and MiTools (v1.5) ( 85 ).…”

Section: Methodsmentioning

confidence: 99%

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

et al. 2022

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Memory B cells (MBCs) and plasma antibodies against Plasmodium falciparum (Pf) merozoite antigens are important components of the protective immune response against malaria. To gain understanding of how responses against Pf develop in these two arms of the humoral immune system, we evaluated MBC and antibody responses against the most abundant merozoite antigen, full-length Pf merozoite surface protein 1 (PfMSP1FL), in individuals from a region in Uganda with high Pf transmission. Our results showed that PfMSP1FL-specific B cells in adults with immunological protection against malaria were predominantly IgG+ classical MBCs, while children with incomplete protection mainly harbored IgM+ PfMSP1FL-specific classical MBCs. In contrast, anti-PfMSP1FL plasma IgM reactivity was minimal in both children and adults. Instead, both groups showed high plasma IgG reactivity against PfMSP1FL, with broadening of the response against non-3D7 strains in adults. The B cell receptors encoded by PfMSP1FL-specific IgG+ MBCs carried high levels of amino acid substitutions and recognized relatively conserved epitopes on the highly variable PfMSP1 protein. Proteomics analysis of PfMSP119-specific IgG in plasma of an adult revealed a limited repertoire of anti-MSP1 antibodies, most of which were IgG1 or IgG3. Similar to B cell receptors of PfMSP1FL-specific MBCs, anti-PfMSP119 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 Pf exposure, with a shift from IgM+ to IgG+ B cell memory, diversification of B cells from germline, and stronger recognition of PfMSP1 variants by the plasma IgG repertoire.

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“…These cells are characterized by the expression of inhibitory markers, and they can be activated by inflammatory signals, such as IFNγ and TLR-9 activation by parasite DNA (reviewed in [ 380 ]). Recent data suggests that AtMBCs or IgM producing MBCs may be part of a normal memory immune response in chronically exposed or vaccinated individuals and various questions remain relating to their development and functionality [ 359 , 363 , 380 – 382 ]. In in vitro co-cultures, AtMBCs increase and classical memory B cells contract in the presence of parasites [ 383 ].…”

Section: Twenty-first Century—turning Point In Malaria Researchmentioning

confidence: 99%

Systems biology of malaria explored with nonhuman primates

Galinski

2022

Malar J

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Abstract“The Primate Malarias” book has been a uniquely important resource for multiple generations of scientists, since its debut in 1971, and remains pertinent to the present day. Indeed, nonhuman primates (NHPs) have been instrumental for major breakthroughs in basic and pre-clinical research on malaria for over 50 years. Research involving NHPs have provided critical insights and data that have been essential for malaria research on many parasite species, drugs, vaccines, pathogenesis, and transmission, leading to improved clinical care and advancing research goals for malaria control, elimination, and eradication. Whilst most malaria scientists over the decades have been studying Plasmodium falciparum, with NHP infections, in clinical studies with humans, or using in vitro culture or rodent model systems, others have been dedicated to advancing research on Plasmodium vivax, as well as on phylogenetically related simian species, including Plasmodium cynomolgi, Plasmodium coatneyi, and Plasmodium knowlesi. In-depth study of these four phylogenetically related species over the years has spawned the design of NHP longitudinal infection strategies for gathering information about ongoing infections, which can be related to human infections. These Plasmodium-NHP infection model systems are reviewed here, with emphasis on modern systems biological approaches to studying longitudinal infections, pathogenesis, immunity, and vaccines. Recent discoveries capitalizing on NHP longitudinal infections include an advanced understanding of chronic infections, relapses, anaemia, and immune memory. With quickly emerging new technological advances, more in-depth research and mechanistic discoveries can be anticipated on these and additional critical topics, including hypnozoite biology, antigenic variation, gametocyte transmission, bone marrow dysfunction, and loss of uninfected RBCs. New strategies and insights published by the Malaria Host–Pathogen Interaction Center (MaHPIC) are recapped here along with a vision that stresses the importance of educating future experts well trained in utilizing NHP infection model systems for the pursuit of innovative, effective interventions against malaria.

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B Cell Receptor Repertoire Analysis in Malaria-Naive and Malaria-Experienced Individuals Reveals Unique Characteristics of Atypical Memory B Cells

Cited by 13 publications

References 61 publications

Atypical B cells up-regulate costimulatory molecules during malaria and secrete antibodies with T follicular helper cell support

Atypical B cells up-regulate costimulatory molecules during malaria and secrete antibodies with T follicular helper cell support

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

Systems biology of malaria explored with nonhuman primates

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