Neeta Thawani, Mifong Tam, Marie-Josée Bellemare, D. Scott Bohle, Martin Olivier, J. Brian de Souza and Mary M. Stevenson
Low reticulocytosis, indicating reduced red blood cell (RBC) output, is an important feature of severe malarial anemia. Evidence supports a role for Plasmodium products, especially hemozoin (Hz), in suppressed erythropoiesis during malaria, but the mechanism(s) involved remains unclear. Here, we demonstrated that low reticulocytosis and suppressed erythropoietin (Epo)-induced erythropoiesis are features of malarial anemia in P. yoelii- and P. berghei ANKA-infected mice similar to our previous observations in P. chabaudi AS-infected mice. The magnitude of decreases in RBC was a reflection of parasitemia level, but low reticulocytosis was evident despite differences in parasitemia, clinical manifestation, and infection outcome. Schizont extracts and Hz from P. falciparum and P. yoelii and synthetic Hz suppressed Epo-induced proliferation of erythroid precursors in vitro, but did not inhibit RBC maturation. To determine if Hz contributes to malarial anemia, P. yoelii-derived or synthetic Hz was administered to naïve mice and the development of anemia, reticulocytosis, and RBC turnover were determined. Parasite-derived Hz induced significant decreases in RBC and increased RBC turnover with compensatory reticulocytosis, but anemia was not as severe as that in infected mice. Our findings suggest that parasite factors, including Hz, contribute to severe malarial anemia by suppressing Epo-induced proliferation of erythroid precursors.