Abstract
Protective immunity to blood-stage malaria is attributed to Plasmodium-specific IgG and effector-memory T helper 1 (Th1) cells. However, mice lacking the costimulatory receptor CD28 (CD28KO) maintain chronic parasitemia at low levels and do not succumb to infection, suggesting that other immune responses contribute to parasite control. We report here that CD28KO mice develop long-lasting non-sterile immunity and survive lethal parasite challenge. This protection correlated with a progressive increase of anti-parasite IgM serum levels during chronic infection. Serum IgM from chronically infected CD28KO mice recognize erythrocytes infected with mature parasites, and effectively control Plasmodium infection by promoting parasite lysis and uptake. These antibodies also recognize autoantigens and antigens from other pathogens. Chronically infected CD28KO mice have high numbers of IgM+ plasmocytes and experienced B cells, exhibiting a germinal-center independent Fas+GL7-CD38+CD73- phenotype. These cells are also present in chronically infected C57BL/6 mice although in lower numbers. Finally, IgM+ experienced B cells from cured C57BL/6 and CD28KO mice proliferate and produce anti-parasite IgM in response to infected erythrocytes. This study demonstrates that CD28 deficiency results in the generation of germinal-center independent IgM+ experienced B cells and the production of protective IgM during experimental malaria, providing evidence for an additional mechanism by which the immune system controls Plasmodium infection.
Highlights
Protection against clinical blood-stage malaria in humans and mice typically involves parasitespecific IgG antibody production [1][2]
We evaluated the role of IgM produced in response to experimental malaria using chronically infected CD28KO mice as a model, which showed increased parasitemia due to a defect in developing classic memory T and B cells [14]
The protective immunity in CD28KO mice is associated with a progressive increase in anti-parasite and total IgM and, notably, these antibodies recognize Plasmodium chabaudi (Pc)-iRBCs and promote parasite clearance
Summary
Protection against clinical blood-stage malaria in humans and mice typically involves parasitespecific IgG antibody production [1][2]. Data from mouse malaria models suggest that. HBdS received a PhD fellowship from FAPESP (2009/08559-1). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript
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