Dissecting Malarial Anemia Using Rodent Malaria Models

Abstract

Malaria continues to be a global issue, with many deaths arising from severe malaria anemia. Rodent malaria models are a well-known tool for studying malaria disease pathology. Initial microarray data revealed changes to erythropoiesis, the production of red blood cells (RBC), with increased erythropoietic pathways for Plasmodium yoelii yoelii 17XNL infected mice and decreased erythropoietic pathways for Plasmodium yoelii nigeriensis N67C infected mice. These two rodent malaria models were utilized to dissect and identify molecular mechanisms of RBC clearance and inhibition of erythropoiesis, both which contribute to anemia. The 17XNL infected mice displayed anemia with lower levels of hematocrit, hemoglobin, and total blood cells. There was a dramatic reduction in mature RBCs, even though the 17XNL parasites preferentially infected reticulocytes (the differentiation stage before RBCs). 17XNL infected mice also displayed splenomegaly and induced erythropoiesis; however, there likely was a blockage of complete erythropoiesis to produce RBCs. The erythroblastic island (EBI) macrophages, involved in erythropoiesis, showed decreased levels of CD163 and CD169, and parasite hemozoin was found near EBIs through histology analysis. These EBI changes as well as the increases in pro-inflammatory cytokines likely contributed to the EBI macrophages being unable to support RBC production even though erythropoiesis was induced for the 17XNL infection model. In contrast, the N67C infection model decreased erythropoietic pathways, with less erythropoiesis occurring in the bone marrow and spleen. Reduced erythropoiesis was also demonstrated through lower levels of GATA1 (a transcription factor) and decreases in the number of reticulocytes for the N67C infected mice. The N67C infected mice also became anemic with a high number of infected and uninfected RBCs cleared possibly through phagocytosis. High levels of pro-inflammatory cytokines as well as decreased levels of IL-10 and IL-12 probably contributed to the changes in erythropoiesis for the N67C infection model. The increased cytokine levels and splenic immune cell death alongside the decreases in erythropoiesis all likely contributed to host death for the N67C infected mice. Overall, this study provides a further understanding of malaria induced anemia pathways, which is useful to develop new treatment avenues as many people are still globally affected by severe malaria anemia.