Bartman Caroline R, Hou Shengqi, Correa Fabian, Shen Yihui, da Silva-Diz Victoria, Aleksandrova Maya, Herranz Daniel, Rabinowitz Joshua D, Intlekofer Andrew M
Department of Chemistry, Princeton University, Princeton, NJ, USA; Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ, USA; Ludwig Institute for Cancer Research, Princeton University, Princeton, NJ, USA; Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, PA, USA.
Human Oncology & Pathogenesis Program and Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Mol Metab. 2025 Jun 26;99:102194. doi: 10.1016/j.molmet.2025.102194.
Viral infection of cells leads to metabolic changes, but how viral infection changes whole-body and tissue metabolism in vivo has not been comprehensively studied. In particular, it is unknown how metabolism might be differentially affected by an acute infection that the immune system can successfully clear compared to a chronic persistent infection.
Here we used metabolomics and isotope tracing to identify metabolic changes in mice infected with acute or chronic forms of lymphocytic choriomeningitis virus (LCMV) for three or eight days.
Both types of infection alter metabolite levels in blood and tissues, including itaconate and thymidine. However, we observed more dramatic metabolite changes in the blood and tissues of mice with persisting LCMV infection compared to those infected with the acute viral strain. Isotope tracing revealed that the contribution of both glucose and glutamine to the tricarboxylic acid (TCA) cycle increase in the spleen, liver, and kidneys of mice infected with chronic LCMV, while acute LCMV only increases the contribution of glutamine to the TCA cycle in the spleen. We found that whole-body turnover of both glutamine and thymidine increase during acute and chronic infection, whereas whole-body glucose turnover surprisingly does not change. Activated T cells in vitro produce thymidine and virus-specific T cells ex vivo have increased thymidine levels, nominating T lymphocytes as the source of thymidine in LCMV infection.
In sum, we provide comprehensive measurements of whole-body and tissue metabolism in acute and chronic viral infection, and identify altered thymidine metabolism as a marker of viral infection.
病毒感染细胞会导致代谢变化，但病毒感染如何在体内改变全身和组织代谢尚未得到全面研究。特别是，与慢性持续性感染相比，免疫系统能够成功清除的急性感染对代谢的影响方式尚不清楚。
在此，我们使用代谢组学和同位素示踪技术，来确定感染急性或慢性淋巴细胞性脉络丛脑膜炎病毒（LCMV）三天或八天的小鼠的代谢变化。
两种类型的感染都会改变血液和组织中的代谢物水平，包括衣康酸和胸苷。然而，与感染急性病毒株的小鼠相比，我们在持续感染LCMV的小鼠的血液和组织中观察到了更显著的代谢物变化。同位素示踪显示，在感染慢性LCMV的小鼠的脾脏、肝脏和肾脏中，葡萄糖和谷氨酰胺对三羧酸（TCA）循环的贡献均增加，而急性LCMV感染仅增加了脾脏中谷氨酰胺对TCA循环的贡献。我们发现，在急性和慢性感染期间，谷氨酰胺和胸苷的全身周转率均增加，而全身葡萄糖周转率出人意料地没有变化。体外活化的T细胞会产生胸苷，离体的病毒特异性T细胞的胸苷水平升高，表明T淋巴细胞是LCMV感染中胸苷的来源。
总之，我们提供了急性和慢性病毒感染中全身和组织代谢的综合测量结果，并确定胸苷代谢改变是病毒感染的一个标志物。
