Sex-specific Schistosomiasis induced metabolic modulation of the myeloid lineage. Sex-specific Schistosomiasis induced metabolic modulation of the myeloid lineage

Despite strong evidence that prior helminth infection exerts a protective effect against the development of metabolic disease, a major gap exists in understanding the mechanism(s) underlying this protection. We previously found that Schistosoma mansoni infection induces dramatic transcriptional alterations in hepatic macrophage metabolism, and that this correlates with protection from high fat diet (HFD) induced atherosclerosis and glucose intolerance in male ApoE-/- mice. We sought in the present study to determine the broad effects of S. mansoni exposure on the myeloid lineage using the ApoE-/- HFD model. We uncovered that macrophages derived from the bone marrow of S. mansoni infected male mice have dramatically increased oxygen consumption and mitochondrial mass compared to those from uninfected mice. This shift is accompanied by increased glucose shuttling into TCA cycle intermediates and decreased cholesterol esters. When we examined the role of biological sex in schistosome induced modulation. We found that S. mansoni infection does not reliably protect ApoE-/- female mice from HFD induced weight gain or glucose intolerance. The sex-dependent effect of infection extends to myeloid precursors, where the metabolic phenotype of bone marrow derived macrophages from infected females are the opposite of those from infected males. Overall, these data present the first evidence that S. mansoni systemically modulates the myeloid compartment in a sex-dependent manner. Overall design: mRNAseq of BMDM from 4 uninfected male ApoE-/- mice on HFD, 5 schistosoma mansoni infected male ApoE-/- mice on HFD, 4 uninfected female ApoE-/- mice on HFD, 5 Schistosoma mansoni infected. All samples are from 10 week post infection/mock infection ApoE-/- mice on HFD

尽管已有充分证据表明，既往蠕虫感染可对代谢性疾病的发生发挥保护作用，但目前学界对该保护作用背后的核心机制仍存在显著认知空白。本团队此前研究发现，曼氏血吸虫（Schistosoma mansoni）感染可引发肝巨噬细胞代谢的显著转录组改变，且该改变与雄性ApoE敲除（ApoE-/-）小鼠免受高脂饮食（high fat diet, HFD）诱导的动脉粥样硬化及葡萄糖耐受不良的表型相关。本研究旨在借助ApoE-/-小鼠高脂饮食模型，明确曼氏血吸虫暴露对髓系细胞谱系的整体调控效应。研究发现，相较于未感染小鼠，曼氏血吸虫感染雄性小鼠的骨髓源性巨噬细胞（bone marrow derived macrophages, BMDM）耗氧量与线粒体质量均显著升高；该代谢重塑伴随葡萄糖向三羧酸循环（tricarboxylic acid cycle, TCA）中间产物的转运增强，同时胆固醇酯水平降低。在探究生物性别在血吸虫诱导的代谢调控中的作用时，我们发现曼氏血吸虫感染无法有效保护雌性ApoE-/-小鼠免受高脂饮食诱导的体重增加与葡萄糖耐受不良。感染带来的性别依赖性效应还延伸至髓系前体细胞：受感染雌性小鼠的骨髓源性巨噬细胞代谢表型与受感染雄性小鼠完全相反。综上，本研究数据首次证实，曼氏血吸虫可通过性别依赖性方式系统性调控机体髓系细胞库。整体实验设计：对高脂饮食喂养的4只未感染雄性ApoE-/-小鼠、5只曼氏血吸虫感染雄性ApoE-/-小鼠、4只未感染雌性ApoE-/-小鼠以及5只曼氏血吸虫感染雌性ApoE-/-小鼠的骨髓源性巨噬细胞进行mRNA测序。所有样本均取自高脂饮食喂养且感染/模拟感染10周后的ApoE-/-小鼠。