Abstract: The vast majority of Plasmodium falciparum infections are either asymptomatic (creating a reservoir for ongoing transmission) or lead to an uncomplicated febrile illness. Only a small proportion of infections progress to life-threatening malaria disease. The relative contributions of the malaria parasite and the human host to this disease severity spectrum have not been well described. This project will establish two cohorts of children to investigate factors that influence the dynamics of infection progression. One cohort will identify subjects at both ends of the disease severity spectrum (cerebral malaria patients with retinopathy and increased brain volume at the severe end, and participants that have remained asymptomatically infected for two months at the mild end) to compare factors that lead to differences in disease severity; the other cohort will capture children transitioning from asymptomatic malaria infection to malaria disease. Both sets of clinical samples will be used to test four hypotheses; two related to parasite characteristics (the speed of replication and the genetic complexity of the infection), and two related to the human host (the intensity of the inflammatory response and the antibody responses to a family of proteins, the variable surface antigens). Using the two comparison groups and these four hypotheses, we will be able to gain new insights into the possible causes of the different outcomes of malaria infection. These insights should not only aid in designing new treatments for those children suffering from severe disease, but could also help in planning for interventions that will eliminate infection from the asymptomatically-infected children contributing to the transmission reservoir.