Mathematical Biology Seminar Rustom Antia Department of Biology, Emory University Wednesday Nov. 8, 2006 3:05pm in LCB 215 "What determines the virulence of malaria? (Bringing mathematical models of the within-host dynamics of malaria into risky contact with experimental data.)" Abstract: Why is malaria virulent? Despite causing over a million deaths a year the mechanisms by which the malaria parasite causes disease are still poorly understood. A central problem has been to understand what determines the level of virulence during the initial phase of acute primary infections when pathology due to the loss of red blood cells is greatest. There are many hypotheses: the conventional view is that the fastest replicating parasites have the highest virulence; alternatives are that parasites that infect the youngest red blood cells (reticulocytes), or that elicit relatively weak immune responses, are most virulent. Here we present the new hypothesis that virulence is proportional to the fraction of red blood cells that the malaria parasites can infect. We discriminate between this and the earlier hypotheses by developing a mathematical model of acute malaria infections and confronting it with experimental data from the rodent malaria Plasmodium chabaudi. We show that our model can explain the dynamics of single-strain infections. We further test the model by showing that without modification it closely reproduces the dynamics of competing strains in mixed infections. Importantly, our results allow us to explain why the earlier hypotheses fail. Our results suggest that the virulence of acute malaria infections is determined almost exclusively by how wide an age range of red blood cells malaria strains can infect.