Targeting anemia-induced CD71 ⁺ reticulocytes protects mice from <i>Plasmodium</i> infection

Malaria, caused by <i>Plasmodium</i> spp., is a global health concern linked to anemia and increased mortality. Compensatory erythropoiesis seen during acute anemia results in an increased circulating reticulocyte count (i.e., immature RBC), a key factor in understanding the relationship between pre-existing anemia and <i>Plasmodium</i> burden. Reticulocytes in mice are marked by transferrin receptor (CD71⁺) and glycophorin A-associated protein (Ter119⁺). To model acute anemia with increased reticulocytes, C57BL/6J mice were either bled (i.e., phlebotomized) or administered phenylhydrazine before being infected with <i>Plasmodium yoelii</i> (<i>P. yoelii</i>), a mouse-specific strain with a preference for reticulocytes. In <i>P. yoelii</i>-infected anemic mice, we observed heightened parasitemia and significant body weight loss compared with non-anemic <i>P. yoelii</i>-infected mice. Additionally, serum inflammatory cytokines, erythropoietin, and liver injury markers, along with hemozoin deposition, significantly increased in anemic <i>P. yoelii</i>-infected mice. Blood transfusion from healthy normal donors to <i>P. yoelii</i>-infected anemic recipient mice ameliorated anemia by reducing overall reticulocyte count and increasing mature RBC count. Blood transfusion rescued body weight loss, decreased parasitemia, and reduced serum erythropoietin levels. Finally, to confirm the role of reticulocytes in <i>P. yoelii</i> infection, reticulocytes were depleted using anti-CD71 monoclonal antibody in <i>P. yoelii</i>-infected mice. We observed improvement in hematologic parameters and stark reduction in parasitemia in both pre-existing anemic and non-anemic <i>P. yoelii</i>-infected mice. Collectively, our results suggest that pre-existing anemia may increase the risk of <i>Plasmodium</i> infection due to the greater reticulocyte population. Anti-CD71 treatment in <i>Plasmodium</i> infection may offer a novel therapeutic strategy to combat <i>Plasmodium</i> infection and malaria.