PT - JOURNAL ARTICLE AU - Christine S. Hopp AU - Ababacar Diouf AU - Kazutoyo Miura AU - Kristin Boswell AU - Padmapriya Sekar AU - Jeff Skinner AU - Christopher M. Tipton AU - Michael Chambers AU - Sarah Andrews AU - Joshua Tan AU - Shanping Li AU - Safiatou Doumbo AU - Kassoum Kayentao AU - Aissata Ongoiba AU - Boubacar Traore AU - Silvia Portugal AU - Carole Long AU - Richard A. Koup AU - Eric Long AU - Adrian B. McDermott AU - Peter D. Crompton TI - <em>Plasmodium falciparum</em>-specific IgM B cells dominate in children, expand with malaria and produce parasite inhibitory IgM AID - 10.1101/2020.04.12.030049 DP - 2020 Jan 01 TA - bioRxiv PG - 2020.04.12.030049 4099 - http://biorxiv.org/content/early/2020/04/12/2020.04.12.030049.short 4100 - http://biorxiv.org/content/early/2020/04/12/2020.04.12.030049.full AB - IgG antibodies are known to play a central role in naturally acquired immunity to blood-stage malaria in humans, but little is known about the IgM response to blood-stage malaria, the mechanisms by which IgM may protect, or the underlying biology of Plasmodium falciparum (Pf)-specific IgM B cells. In a Mali cohort spanning infants to adults we conducted a longitudinal analysis of B cells specific for the Pf blood-stage antigens AMA1 and MSP1, as well as the comparator antigen influenza hemagglutinin (HA). At the uninfected baseline, before the malaria season, Pf-specific memory B cells (MBCs) in children are disproportionally IgM+ and only gradually shift to IgG+ with age, in contrast to HA-specific MBCs that are predominantly IgG+ from infancy to adulthood. In response to acute febrile malaria, Pf-specific IgM B cells increase in frequency and upregulate activation and co-stimulatory markers. B cell receptor (BCR) analysis showed that Pf-specific IgM B cells are somatically hypermutated at levels comparable to HA-specific IgG B cells. Finally, IgM antibodies from the plasma of malaria-exposed individuals were comparable to IgG in inhibiting Pf blood-stage growth in vitro, and significantly better at enhancing phagocytosis of Pf merozoites, suggesting that IgM may protect through both direct neutralization and opsonization. Thus, somatically hypermutated Pf-specific IgM MBCs dominate in early life, are activated and expand during acute malaria and are associated with plasma IgM that inhibits parasite growth in vitro.Competing Interest StatementThe authors have declared no competing interest.