Schistosome antigen induced modulation of metabolism

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Project Summary Globally, parasitic helminth infections inversely correlate with metabolic diseases, such as diabetes, atherosclerosis, and obesity, but the parasite factors that are capable of modulating metabolic disease are currently unknown. Diabetic patients are twice as likely as non-diabetic individuals to develop cardiovascular disease, with more than 65% of diabetic patients dying from cardiovascular complications, thus there is a critical need for identifying novel compounds capable of modulating insulin resistance, obesity, and atherosclerosis in this population. Recent evidence has suggested that inflammation driven by macrophages is associated with both obesity and insulin resistance, while atherosclerosis is accepted to be driven by lipid- dependent chronic myeloid inflammation. Our laboratory has recently identified that Schistosoma mansoni infection modulates the metabolic transcriptome of the myeloid lineage, and that this modulation is correlated with protection from the development of insulin resistance, diabetes, and atherosclerosis in the ApoE-/- high fat diet mouse model. Our lab and others have established that in vivo metabolic protection is dependent on exposure to egg antigens, but the antigens sufficient to confer protection are unknown. To fill these current knowledge gaps, we propose to perform proteomic analysis and screening to identify the antigens sufficient to modulate macrophage metabolism. We will first 1) identify pools of antigens sufficient to modulate mature bone marrow derived macrophage metabolism, and then 2) determine the subset of antigens sufficient to program bone marrow precursors to generate immunomodulated macrophages in vivo. The data generated from these studies will lay the foundation for future studies on understanding the role of helminth induced macrophages in the long-term regulation of whole-body metabolism.