Department of Molecular and Cellular Medicine, Texas A&M University, College of Medicine, Bryan, TX 77807, USA.
Department of Molecular and Cellular Medicine, Texas A&M University, College of Medicine, Bryan, TX 77807, USA.
Cell Metab. 2021 Dec 7;33(12):2428-2444.e8. doi: 10.1016/j.cmet.2021.10.003. Epub 2021 Oct 27.
Individual hosts within populations often show inter-individual variation in their susceptibility to bacterial pathogen-related diseases. Utilizing Drosophila, we highlight that phenotypic variation in host-pathogen susceptibility within populations is driven by energetic trade-offs, facilitated by infection-mediated changes in glutamate metabolism. Furthermore, host-pathogen susceptibility is conditioned by life history, which adjusts immunometabolic sensing in muscles to direct vitamin-dependent reallocation of host energy substrates from the adipose tissue (i.e., a muscle-adipose tissue axis). Life history conditions inter-individual variation in the activation strength of intra-muscular NF-κB signaling. Limited intra-muscular NF-κB signaling activity allows for enhanced infection-mediated mitochondrial biogenesis and function, which stimulates glutamate dehydrogenase-dependent synthesis of glutamate. Muscle-derived glutamate acts as a systemic metabolite to promote lipid mobilization through modulating vitamin B enzymatic cofactor transport and function in the adipose tissue. This energy substrate reallocation improves pathogen clearance and boosts host survival. Finally, life history events that adjust energetic trade-offs can shape inter-individual variation in host-pathogen susceptibility after infection.
在种群中，个体宿主在对与细菌病原体相关疾病的易感性方面通常表现出个体间的差异。利用果蝇，我们强调了种群内宿主-病原体易感性的表型变异是由能量权衡驱动的，这是由感染介导的谷氨酸代谢变化所促进的。此外，宿主-病原体易感性受生活史条件的影响，生活史调节肌肉中的免疫代谢感应，以指导宿主能量底物从脂肪组织（即肌肉-脂肪组织轴）的维生素依赖性再分配。生活史条件会影响肌肉内 NF-κB 信号转导的激活强度的个体间变异。有限的肌肉内 NF-κB 信号转导活性允许增强感染介导的线粒体生物发生和功能，这刺激了谷氨酸脱氢酶依赖性谷氨酸的合成。肌肉衍生的谷氨酸作为一种系统代谢物，通过调节脂肪组织中维生素 B 酶辅因子的运输和功能，促进脂质动员。这种能量底物再分配可提高病原体清除率并提高宿主存活率。最后，调整能量权衡的生活史事件可以在感染后塑造宿主-病原体易感性的个体间变异。
