Defining the Inflammation and Immunity Transcriptome in Severe Malarial Anemia for Immunotherapeutic Discovery

Malaria continues to pose a significant public health threat, with millions of cases and hundreds of thousands of deaths reported annually, primarily in sub-Saharan Africa. The disease disproportionally affects children under five years of age residing in holoendemic Plasmodium falciparum transmission regions, who account for 94% of the cases and 80% of the mortality. Young children are highly vulnerable to developing life-threatening severe malarial anemia [SMA, hemoglobin (Hb)<5.0 g/dL]. The overall goal of the project was to identify critical gene pathways within the transcriptome that mediate disease severity and then target these specific genes with compounds that elicit expression profiles witnessed in children with milder forms of disease. To achieve this goal, we are investing the following specific aims: 1) Determine how changing temporal dynamics of gene pathways in the Malarial Immunity Transcriptome promote SMA during acute disease; 2) Determine how changes in gene pathways in the Malarial Immunity Transcriptome mediate malarial severity throughout the development of naturally acquired immunity; and 3) Identify immunotherapeutic targets in the Malarial Immunity Transcriptome that can be used to reduce malaria disease severity and improve clinical outcomes in future trials. To successfully complete these aims, we are determining how host profiles impact on acute disease over 14 days. We will utilize Ex vivo samples from the cohort to test the effect of immunotherapeutic compounds on host expression profiles. Accomplishing these goals will have broad reaching translational implications for: (1) identifying at-risk groups, and (2) prioritizing compounds that can be used to improve clinical outcomes in future immunotherapy trials.