Host Control of Malaria Infections: Constraints on Immune and Erythropoeitic Response Kinetics

The two main agents of human malaria, Plasmodium vivax and Plasmodium falciparum, can induce severe anemia and provoke strong, complex immune reactions. Which dynamical behaviors of host immune and erythropoietic responses would foster control of infection, and which would lead to runaway parasitemia and/or severe anemia? To answer these questions, we developed differential equation models of interacting parasite and red blood cell (RBC) populations modulated by host immune and erythropoietic responses. The model immune responses incorporate both a rapidly responding innate component and a slower-responding, long-term antibody component, with several parasite developmental stages considered as targets for each type of immune response. We found that simulated infections with the highest parasitemia tended to be those with ineffective innate immunity even if antibodies were present. We also compared infections with dyserythropoiesis (reduced RBC production during infection) to those with compensatory erythropoiesis (boosted RBC production) or a fixed basal RBC production rate. Dyserythropoiesis tended to reduce parasitemia slightly but at a cost to the host of aggravating anemia. On the other hand, compensatory erythropoiesis tended to reduce the severity of anemia but with enhanced parasitemia if the innate response was ineffective. For both parasite species, sharp transitions between the schizont and the merozoite stages of development (i.e., with standard deviation in intra-RBC development time ≤2.4 h) were associated with lower parasitemia and less severe anemia. Thus tight synchronization in asexual parasite development might help control parasitemia. Finally, our simulations suggest that P. vivax can induce severe anemia as readily as P. falciparum for the same type of immune response, though P. vivax attacks a much smaller subset of RBCs. Since most P. vivax infections are nonlethal (if debilitating) clinically, this suggests that P. falciparum adaptations for countering or evading immune responses are more effective than those of P. vivax.Author Summary: Of the four Plasmodium species that parasitize human erythrocytes and induce malaria, Plasmodium falciparum and Plasmodium vivax cause most of the public health burden. P. falciparum infection is typically characterized as “malignant” (due to severe, sometimes lethal consequences, particularly in immune-naïve individuals), and P. vivax malaria as (relatively) “benign.” Using the power of a Beowulf cluster, we tested hypotheses about host control of malaria by simulating ∼8.4×104 combinations of parasite species, host immune response, and erythropoietic response to infection. We tailored the models to specific details of the life cycles of the two species, which invade different subclasses of red blood cells. Our results challenge some standard assumptions. For example, we show that tight synchronization of the asexual reproduction of malaria parasites may actually benefit the host by reducing parasitemia. We also demonstrate that properties of host immunity or erythropoiesis that contribute to high parasitemia and severe anemia in P. falciparum malaria would do so in P. vivax infection as well, in line with recent reports indicating that P. vivax can indeed cause “malignant” illness in some patients. This suggests that P. falciparum is more effective overall at immune evasion or suppression than P. vivax.