PROJECT SUMMARY Diabetic patients have a two-fold greater risk of developing cardiovascular disease than non-diabetic subjects, and more than 65% of diabetic patients die from cardiovascular complications, thus, there is a critical need for novel approaches to targeting insulin resistance, obesity, and atherosclerosis in this population. Recent evidence has suggested that innate and/or adaptive inflammatory responses are associated with both insulin resistance and obesity, while atherosclerosis is now widely accepted to be a lipid-dependent chronic inflammatory disease. An increasing body of literature has established an inverse correlation between chronic helminth infections and metabolic syndrome/diabetes. The central hypothesis of this project is that schistosome antigenic exposure induces long-lived modifications in the monocyte/macrophage lineage that lead to profound alterations in systemic phospholipid, cholesterol, and amino acid metabolism, resulting in a protective state from the detrimental effects of High Fat Diet (HFD) (e.g., insulin insensitivity, and atherosclerosis). The rationale for this research is that identifying genetic drivers that underlie this protective phenotype is expected to enable the formulation and development of therapies to target these pathways as treatments for diabetic patients at risk for CVD. This objective will be addressed by pursuing three specific aims: 1) Define the role of S. mansoni infection in regulating the long-term metabolic and immunological function of macrophages; 2) Determine how S. mansoni infection regulates hematopoietic differentiation of macrophages at the transcriptional level; and 3) Determine the role of biological sex and sex hormones in schistosome induced metabolic reprogramming. It is expected that the findings from these studies will provide a definitive conceptual framework as to the mechanism through which S. mansoni infection modulates metabolism and immunologic plasticity of the macrophage lineage.