A metabolic dependency of EBV can be targeted to hinder B cell transformation

• 成果类型: Article
• 署名作者: Mueller-Durovic, Bojana; Jager, Jessica; Engelmann, Christine; Schuhmachers, Patrick; Altermatt, Sabine; Schlup, Yannick; Duthaler, Urs; Makowiec, Celia; Unterstab, Gunhild; Roffeis, Sarah; Xhafa, Erta; Assmann, Nadine; Trulsson, Fredrik; Steiner, Rebekah; Edwards-Hicks, Joy; West, James; Turner, Lorinda; Develioglu, Leyla; Ivanek, Robert; Azzi, Tarik; Dehio, Philippe; Berger, Christoph; Kuzmin, Dmitry; Saboz, Sophie; Mautner, Josef; Loliger, Jordan; Geigges, Marco; Palianina, Darya; Khanna, Nina; Dirnhofer, Stefan; Munz, Christian; Bantug, Glenn R.; Hess, Christoph
• 署名单位: University of Basel; University of Basel; University of Zurich; University of Basel; University of Cambridge; University of Basel; University Children's Hospital Zurich; University Children's Hospital Zurich; Yale University; Helmholtz Association; Helmholtz-Center Munich - German Research Center for Environmental Health; University of Basel; University of Basel; Novartis; Technical University of Munich
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-14019
• DOI: 10.1126/science.adk4898
• 发表日期: 2024-07-05
• 关键词: epstein-barr-virus; cd8(+) t-cells; laboratory strains; infection; immortalization; persistence; lymphocytes; rituximab; package

摘要

After 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 nicotinamide adenine dinucleotide (NAD) de novo biosynthesis by driving expression of the metabolic enzyme indoleamine 2,3-dioxygenase 1 (IDO1) in infected B cells. Virus-enforced NAD production sustained mitochondrial complex I activity, to match adenosine triphosphate (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 therefore a druggable metabolic vulnerability of EBV-driven B cell transformation, opening therapeutic possibilities for EBV-related diseases.