T Cell Memory and Protection Against Placental Malaria

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DESCRIPTION: (provided by the applicant): Women living in high malaria endemic areas are at an increased risk for Plasmodial infection during pregnancy. The prevalence and density of parasitemia is highest among primigravidae, and commonly leads to maternal anemia and low birth weight. The placenta is especially susceptible to infection, with parasite densities being frequently higher than those in the peripheral blood. The underlying immunologic basis for the increased susceptibility of pregnant women (and their placentae) to malaria and the dependence of this susceptibility on gravidity are poorly understood. The objective of this application is to determine the cellular immune mechanisms that mediate resistance to placental malaria. The central hypothesis of this proposal is that the decreased susceptibility of multigravidae to placental infection is dependent on development of tissue-specific, T cell-mediated, memory immune responses against malaria in the placental blood. The specific aims are to 1) to characterize cell-mediated immune memory in the placenta and identify the elements that contribute to protection against placental malaria, and 2) determine the role of chemokines in the regulation of memory immune responses against malarial infection in the placenta. Comparison of peripheral and placental blood collected at delivery using flow cytometry, ELISPOT, ELISA, and RNase protection assays, and examination of placental tissue using immunohistochemistry, will be used to 1) identify the phenotypic and functional components of placental cellular memory responses to malaria that distinguish multigravidae from primigravidae, susceptible women from resistant women, and pathogenic responses from protective responses, 2) determine the extent to which these placental responses are distinct from those in the peripheral blood, and 3) determine how differential, local chemokine expression patterns in the placenta influence memory immune responses to placental malaria. Expanded knowledge of protective, anti-malarial immune mechanisms that are developed and maintained in the immunomodulated state of pregnancy will facilitate application of immunologic tools, such as malaria vaccines when they become available, to the prevention and control of malaria in pregnant women. Preventing malaria in pregnant women will significantly reduce both the disease burden of women in the developing world and the loss of infants in their first few months of life.