Despite strong evidence that helminth infections are protective against the development of metabolic disease, a major gap exists in understanding the mechanism(s) underlying this. We have previously found that Schistosoma mansoni induces profound alterations to the metabolic transcriptome of hepatic macrophages and protects male ApoE -/- on high fat diet from the development of obesity, glucose intolerance, and atherosclerosis. Here we demonstrate that macrophages derived from the bone marrow (BMDM) of S. mansoni infected male ApoE -/- mice have dramatically increased mitochondrial respiration and mitochondrial mass compared to those from uninfected mice. This change is accompanied by increased glucose and palmitate shuttling into TCA cycle intermediates and decreased accumulation of cellular cholesterol esters. The systemic effects of metabolic modulation by schistosome infection are a function of biological sex, where schistosome infection protects ApoE -/- male mice from obesity, glucose intolerance, and increased serum triglycerides, but not female mice. The sex-dependent effects of infection extend to myeloid cells specifically, where metabolic reprogramming leads to opposite cholesterol phenotypes in BMDM from infected females and males. Finally, we demonstrate that the metabolic reprogramming of male myeloid cells is transferrable via bone marrow transplantation to an uninfected host, indicating maintenance of reprogramming in the absence of ongoing schistosome antigen exposure. This work provides strong evidence that S. mansoni systemically reprograms the metabolism of the myeloid compartment in a sex-dependent manner.

中文翻译：

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曼氏血吸虫感染可重新编程小鼠代谢综合征模型中髓系的代谢潜能

尽管有强有力的证据表明蠕虫感染可预防代谢性疾病的发展，但在理解其背后的机制方面仍存在重大差距。先前我们已经发现曼氏血吸虫诱导肝巨噬细胞代谢转录组的深刻改变，并保护高脂饮食的男性ApoE-/-免受肥胖，葡萄糖耐受不良和动脉粥样硬化的发展。在这里，我们证明，与未感染小鼠相比，曼氏链球菌感染的雄性ApoE-/-小鼠的骨髓（BMDM）巨噬细胞具有显着增加的线粒体呼吸作用和线粒体质量。这种变化伴随着增加的葡萄糖和棕榈酸酯穿入TCA循环中间体和减少细胞胆固醇酯的积累。血吸虫感染引起的代谢调节的全身效应是生物学行为的函数，血吸虫感染可以保护ApoE-/-雄性小鼠免于肥胖，葡萄糖耐受不良和血清甘油三酯升高，但不能保护雌性小鼠。感染的性别依赖性效应尤其延伸到髓样细胞，在该细胞中，代谢重编程导致被感染的雌性和雄性BMDM中胆固醇表型相反。最后，我们证明了男性骨髓细胞的代谢重编程可通过骨髓移植转移到未感染的宿主，这表明在没有持续的血吸虫抗原暴露的情况下维持重编程。这项工作提供了有力的证据，表明曼氏链球菌以性别依赖性方式系统性地重编程了髓室的代谢。