# Targeting anemia-induced CD71+ reticulocytes protects mice from Plasmodium infection

## TL;DR

Pre-existing anemia increases malaria risk in mice by boosting reticulocytes, which Plasmodium parasites target, and reducing these cells with anti-CD71 treatment may help fight the infection.

## Contribution

Demonstrates that targeting CD71+ reticulocytes can reduce Plasmodium infection severity in anemic and non-anemic mice.

## Key findings

- Anemic mice infected with Plasmodium yoelii showed higher parasitemia and weight loss compared to non-anemic mice.
- Blood transfusion reduced reticulocyte count and improved outcomes in infected anemic mice.
- Anti-CD71 treatment significantly reduced parasitemia in both anemic and non-anemic infected mice.

## Abstract

Malaria, caused by Plasmodium 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 Plasmodium 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 Plasmodium yoelii (P. yoelii), a mouse-specific strain with a preference for reticulocytes. In P. yoelii-infected anemic mice, we observed heightened parasitemia and significant body weight loss compared with non-anemic P. yoelii-infected mice. Additionally, serum inflammatory cytokines, erythropoietin, and liver injury markers, along with hemozoin deposition, significantly increased in anemic P. yoelii-infected mice. Blood transfusion from healthy normal donors to P. yoelii-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 P. yoelii infection, reticulocytes were depleted using anti-CD71 monoclonal antibody in P. yoelii-infected mice. We observed improvement in hematologic parameters and stark reduction in parasitemia in both pre-existing anemic and non-anemic P. yoelii-infected mice. Collectively, our results suggest that pre-existing anemia may increase the risk of Plasmodium infection due to the greater reticulocyte population. Anti-CD71 treatment in Plasmodium infection may offer a novel therapeutic strategy to combat Plasmodium infection and malaria.