Determinants of Malaria Disease in Malawi, 5U19AIO89683-02, "Competitive Revision

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DESCRIPTION (provided by applicant): Severe malaria (SM) places a disproportionate burden of mortality and death on the children of Sub-Saharan Africa. Death, as a result of SM, is not a direct consequence of parasite load but is associated with excessive inflammatory response(s) in the brain and lungs of SM patients. Parasite-derived activators of the innate immune response, together with inflammatory monocytes, have been implicated in mediating this tissue damage. However, the activation pathways responsible for localized inflammation and compromising the blood brain barrier (BBB) remain to be determined. We propose elucidating the mechanism(s) by: 1. Defining the transcriptional profiles at the sites of damage in tissues from pediatric SM. We propose assembling a transcriptional "road map" of the expression profiles at the sites of tissue damage in the brain and lungs of pediatric SM patients. The expression patterns will be validated by immuno-histological analysis of a broader bank of archived tissues from SM patients. 2. Do hemozoin-loaded peripheral blood monocytes demonstrate the capacity to mediate or exacerbate tissue damage? We will perform transcriptional and functional typing of hemozoin-loaded, peripheral blood monocytes from SM patients to determine whether or not their inflammatory activities correlate with the tissue-damaging pathways elucidated in Specific Aim #1. 3. Can these potentially damaging cells be re-programed by appropriate anti-inflammatory drugs or immune-modulators? We propose in vitro screening of a panel of anti-inflammatory compounds against patients' hemozoin-loaded monocytes to identify compounds capable of defusing the activation cascades that lead to tissue damage and death in SM. The goals of this project are designed to generate a mechanistic understanding of the pathology of disease in the SM patient cohort that is the subject of the parent ICEMR grant.