44 45 Despite strong evidence that helminth infections are protective against the development of 46 metabolic disease, a major gap exists in understanding the mechanism(s) underlying this. We 47 have previously found that Schistosoma mansoni induces profound alterations to the metabolic 48 transcriptome of hepatic macrophages and protects male ApoE -/on high fat diet from the 49 development of obesity, glucose intolerance, and atherosclerosis. Here we demonstrate that 50 macrophages derived from the bone marrow (BMDM) of S. mansoni infected male ApoE -/mice 51 have dramatically increased mitochondrial respiration and mitochondrial mass compared to those 52 from uninfected mice. This change is accompanied by increased glucose and palmitate shuttling 53 into TCA cycle intermediates and decreased accumulation of cellular cholesterol esters. The 54 systemic effects of metabolic modulation by schistosome infection are a function of biological 55 sex, where schistosome infection protects ApoE -/male mice from obesity, glucose intolerance, 56 and increased serum triglycerides, but not female mice. The sex-dependent effects of infection 57 extend to myeloid cells specifically, where metabolic reprogramming leads to opposite 58 cholesterol phenotypes in BMDM from infected females and males. Finally, we demonstrate that 59 the metabolic reprogramming of male myeloid cells is transferrable via bone marrow 60 transplantation to an uninfected host, indicating maintenance of reprogramming in the absence of 61 ongoing schistosome antigen exposure. This work provides strong evidence that S. 62 mansoni systemically reprograms the metabolism of the myeloid compartment in a sex-63 dependent manner. 64 65
Author Summary 66Globally helminth endemic regions have lower incidences of metabolic disease. Schistosomiasis 67 in particular has been shown to protect male mice from the development of atherosclerosis, 68 diabetes and obesity while altering the metabolism of liver macrophages. In this present study we 69 sought to understand if metabolic modulation occurs systemically, and if these effects occur in 70 females as well. We have found for the first time that macrophages generated from bone marrow 71 myeloid progenitors from infected male mice have long-lived increases in their basal metabolism 72 of lipids. We have also found that unlike male mice, female mice infected with Schistosoma 73 mansoni are not protected from the development of diabetes and obesity. S. mansoni infection 74 induces opposite changes to macrophage transcription and metabolism in males and females. 75Importantly we demonstrate that the changes to male macrophage metabolism can be transferred 76to an uninfected host. This suggests that metabolic reprogramming is long-lived without 77 exposure to active infection, and the development of a memory-like phenotype. 78 79 80 Introduction 81 82 Cardiovascular disease (CVD) is the leading worldwide cause of mortality [1, 2]. In the United 83States, 65% of adults diagnosed with diabetes have elevated LDL cholestero...