TY - JOUR
T1 - A metabolic dependency of EBV can be targeted to hinder B cell transformation
AU - Swiss Transplant Cohort Study
AU - Müller-Durovic, Bojana
AU - Jäger, Jessica
AU - Engelmann, Christine
AU - Schuhmachers, Patrick
AU - Altermatt, Sabine
AU - Schlup, Yannick
AU - Duthaler, Urs
AU - Makowiec, Celia
AU - Unterstab, Gunhild
AU - Roffeis, Sarah
AU - Xhafa, Erta
AU - Assmann, Nadine
AU - Trulsson, Fredrik
AU - Steiner, Rebekah
AU - Edwards-Hicks, Joy
AU - West, James
AU - Turner, Lorinda
AU - Develioglu, Leyla
AU - Ivanek, Robert
AU - Azzi, Tarik
AU - Dehio, Philippe
AU - Berger, Christoph
AU - Kuzmin, Dmitry
AU - Saboz, Sophie
AU - Mautner, Josef
AU - Löliger, Jordan
AU - Geigges, Marco
AU - Palianina, Darya
AU - Khanna, Nina
AU - Dirnhofer, Stefan
AU - Münz, Christian
AU - Bantug, Glenn R.
AU - Hess, Christoph
AU - Koller, Michael
AU - Rossi, Simona
AU - Stampf, Susanne
AU - Müller, Nicolas J.
N1 - Publisher Copyright:
Copyright © 2024 the authors, some rights reserved;
PY - 2024/7/5
Y1 - 2024/7/5
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/85197753162
U2 - 10.1126/science.adk4898
DO - 10.1126/science.adk4898
M3 - Article
C2 - 38781354
AN - SCOPUS:85197753162
SN - 0036-8075
VL - 385
JO - Science
JF - Science
IS - 6704
M1 - eadk4898
ER -