Malaria caused by P. falciparum continues to be a global problem with devastating consequences. A greater understanding of the immunologic and parasitologic factors associated with infection and disease is badly needed, and will accelerate the development of highly protective vaccines for both mothers and children. Pregnancy malaria is associated with low birth weight, maternal anemia, and gestational hypertension, and both inflammation and the fetal response to infection may contribute to these poor outcomes. Childhood malaria is a major cause of mortality, and we have found that risk of childhood malaria is related to in utero exposure to pregnancy malaria, as well as other host factors like iron status and constitutive cytokine levels. Pregnancy malaria is caused by a distinct parasite binding phenotype, and as our primary hypothesis in this study we speculate that severe childhood malaria parasites may also have distinct features. A longitudinal cohort study is being conducted in Ouelessebougou, Mali, an area of intense seasonal transmission. Up to 2000 pregnant women and their infants and 2000 children ages 0-3 years will be enrolled and the children followed to age 5 years, with clinical evaluation and periodic venous and peripheral blood samples being obtained. In addition, 2000 febrile children up to age 10 years will be enrolled at the Ouelessebougou district hospital or the Gabriel Toure Pediatric Hospital in Bamako, Mali, with acute and convalescent samples being obtained. Clinical, parasitologic and host response (including immunologic) endpoints will be analyzed using appropriate statistical methods, including possible confounders, to determine factors associated with infection and disease in pregnant women and young children. In order to address the associations of pregnancy malaria and preeclampsia, diastolic blood pressure, hypertension, sFlt1 elevations, and urine proteins will be considered as study outcomes. The primary analysis will be the change in diastolic BP over a 1 month period. Women will have BP measured monthly during pregnancy. The interest is if the women who experience malaria have a different change in diastolic BP 1 month after the malaria episode compared to gestationally matched controls. Similarly, associations of pregnancy malaria to stillbirth and preterm delivery will be analyzed for temporal patterns. To date we have enrolled 1500 women in the study who we are monitoring for malaria, blood pressure, urinary protein measurements, and pregnancy outcomes. 1000 women have given birth and their newborns enrolled in the study, and the children are similarly being followed to document episodes of malaria infection, disease, and severe disease, thereby offering an opportunity to identify the parasite and host factors that contirbute to the risks of infection and disease. Parallel to the field studies being conducted in Mali, scientists at the Twinbrook labs have focused on establishing animal models of malaria pathogenesis and immunity, and interrogating these models to gain basic insights into malaria pathogenesis and immunity. These insights will generate hypotheses for testing in the ongoing field studies in Mali. The animal models being developed include models of pregnancy malaria, severe malaria, liver stage malaria, chronic blood stage malaria, and sexual stage malaria. During the past year, we have established a rhesus model of severe malaria anemia, a rodent model of chronic parasitemia, a rodent model of recrudescent malaria during pregnancy, and finally have established a breeding colony of African thicket rats which are the natural host of the rodent malaria parasites. The African thicket rats will be studied to assess whether the course of malaria in these hosts has more similarities to what is seen in human malaria.

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