研究人员发现，爱泼斯坦-巴尔病毒（EBV）蛋白EBNA2通过驱动受感染B细胞中代谢酶IDO1的表达，启动了NAD的从头生物合成。病毒强制产生的NAD可维持线粒体复合体I的活性，使ATP的产生与增殖和转化的生物能需求相匹配。在移植患者中，受EB病毒感染的B细胞中IDO1的表达以及血清中IDO1活性增加的特征，都先于淋巴瘤的发生。
在感染EBV的人源化小鼠中，抑制IDO1可降低病毒血症和淋巴瘤的发生。因此，病毒协调的NAD生物合成是EBV驱动B细胞转化的一个可成药的代谢漏洞，为EBV相关疾病的治疗提供了可能性。
研究人员表示，EBV感染B细胞后，会与介导细胞增殖和转化的宿主通路发生作用，从而导致病毒倾向于推动免疫失调和淋巴瘤的发生。
附：英文原文
Title: A metabolic dependency of EBV can be targeted to hinder B cell transformation
Author: Bojana Müller-Durovic, Jessica Jger, Christine Engelmann, Patrick Schuhmachers, Sabine Altermatt, Yannick Schlup, Urs Duthaler, Celia Makowiec, Gunhild Unterstab, Sarah Roffeis, Erta Xhafa, Nadine Assmann, Fredrik Trulsson, Rebekah Steiner, Joy Edwards-Hicks, James West, Lorinda Turner, Leyla Develioglu, Robert Ivanek, Tarik Azzi, Philippe Dehio, Christoph Berger, Swiss Transplant Cohort Study#, Dmitry Kuzmin, Sophie Saboz, Josef Mautner, Jordan Lliger, Marco Geigges, Darya Palianina, Nina Khanna, Stefan Dirnhofer, Christian Münz, Glenn R. Bantug, Christoph Hess, Christoph Berger, Christoph Hess, Michael Koller, Simona Rossi, Susanne Stampf, Nicolas J. Müller
Issue&Volume: 2024-05-23
Abstract: Following infection of B cells, Epstein Barr virus (EBV) engages host pathways that mediate cell proliferation and transformation, contributing to the propensity of the virus to drive immune dysregulation and lymphomagenesis. We found that the EBV protein EBNA2 initiates NAD de novo biosynthesis by driving expression of the metabolic enzyme IDO1 in infected B cells. Virus-enforced NAD production sustained mitochondrial complex I activity, to match ATP-production with bioenergetic requirements of proliferation and transformation. In transplant patients, IDO1 expression in EBV-infected B cells, and a serum signature of increased IDO1 activity, preceded development of lymphoma. In humanized mice infected with EBV, IDO1 inhibition reduced both viremia and lymphomagenesis. Virus-orchestrated NAD biosynthesis is, thus, a druggable metabolic vulnerability of EBV-driven B cell transformation—opening therapeutic possibilities for EBV-related diseases.
DOI: adk4898
Source: https://www.science.org/doi/10.1126/science.adk4898