Differences in phenotype between long-lived memory B cells against Plasmodium falciparum merozoite antigens and variant surface antigens

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Abstract

Plasmodium falciparum infections elicit strong humoral immune responses to two main groups of antigens expressed by blood-stage parasites: merozoite antigens that are involved in the erythrocyte invasion process and variant surface antigens that mediate endothelial sequestration of infected erythrocytes. Long-lived B cells against both antigen classes can be detected in the circulation for years after exposure, but have not been directly compared. Here, we studied the phenotype of long-lived memory and atypical B cells to merozoite antigens (MSP1 and AMA1) and variant surface antigens (the CIDRα1 domain of PfEMP1) in Ugandan adults before and after local reduction of P. falciparum transmission. After a median of 1.7 years without P. falciparum infections, the percentage of antigen-specific activated B cells declined, but long-lived antigen-specific B cells were still detectable in all individuals. The majority of MSP1/AMA1-specific B cells were CD95 + CD11c + memory B cells, which are primed for rapid differentiation into antibody-secreting cells, and FcRL5 - T-bet - atypical B cells. On the other hand, most CIDRα1-specific B cells were CD95 - CD11c - memory B cells. CIDRα1-specific B cells were also enriched among a subset of atypical B cells that seem poised for antigen presentation. These results point to differences in how these antigens are recognized or processed by the immune system and how P. falciparum -specific B cells will respond upon re-infection.

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    Reply to the reviewers

    We would like to thank the reviewers for their overall positive assessment of our manuscript. We have used their constructive feedback to substantially improve our manuscript as described below.

    Reviewer #1

    Evidence, reproducibility and clarity

    This study by Reyes at al is a well conducted analysis of memory B cell dynamics of Plasmodium falciparum (Pf) -specific B cell populations over the course of reducing Pf prevalence in ten Ugandan adults. The data is presented well and the authors provide compelling evidence that 1. There is an overall loss of Ag specific B cells with reduction in exposure and 2. Different antigens (MSP1/AMA-1 vs CIDRa-1) …

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    Referee #3

    Evidence, reproducibility and clarity

    The authors analysed the antigen specificity and phenotypes of B cells during high P falciparum transmission and after a period of successful malaria control with IRS in Uganda. The gap between the two sampling time points is close to two years.

    They use antigen probes for MSP1/AMA1 and CIDRalpha1, two antigens expressed at different stages of P. falciparum life cycle-merozoites and infected red cells, respectively. While MSP1/AMA1 are involved in the parasite's invasion of red blood cells, CIDRalpha1 is a domain of PFEMP1, a large family of antigenically variant proteins that mediates the sequestration of infected red cells in …

  3. Note: This preprint has been reviewed by subject experts for Review Commons. Content has not been altered except for formatting.

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    Referee #2

    Evidence, reproducibility and clarity

    Summary:

    In this study, the authors compared long-lived total and antigen (ag)-specific B-cell levels in a cohort of 10 Ugandan malaria patient samples that were collected before and after local reduction of P. falciparum transmission (pre/post-IRS). The focus is on the novel comparison of the two most common malaria antigens: merozoite antigens (MSP1/AMA1) and variant surface antigens (CIDRα1). Using high-parameter spectral flow cytometry, they also characterized the phenotype of the different populations of cells. Their main findings include 1) a decrease in activated but maintenance of resting ag-specific B-cells in the …

  4. Note: This preprint has been reviewed by subject experts for Review Commons. Content has not been altered except for formatting.

    Learn more at Review Commons


    Referee #1

    Evidence, reproducibility and clarity

    This study by Reyes at al is a well conducted analysis of memory B cell dynamics of Plasmodium falciparum (Pf) -specific B cell populations over the course of reducing Pf prevalence in ten Ugandan adults. The data is presented well and the authors provide compelling evidence that 1. There is an overall loss of Ag specific B cells with reduction in exposure and 2. Different antigens (MSP1/AMA-1 vs CIDRa-1) generate different flavors of long lived responses. However, additional clarity to the reader should be provided on certain topics (listed below).

    Major comments:

    1. While the premise of the study (reduced Pf transmission due to the …