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

Bojana Müller-Durovic¹, Jessica Jäger^#¹, Christine Engelmann^#², Patrick Schuhmachers², Sabine Altermatt¹, Yannick Schlup¹, Urs Duthaler³, Celia Makowiec¹, Gunhild Unterstab¹, Sarah Roffeis¹, Erta Xhafa¹, Nadine Assmann^{1

4}, Fredrik Trulsson¹, Rebekah Steiner¹, Joy Edwards-Hicks⁵, James West⁵, Lorinda Turner⁵, Leyla Develioglu¹, Robert Ivanek⁶, Tarik Azzi^{7

8}, Philippe Dehio¹, Christoph Berger⁷; Swiss Transplant Cohort Study; Dmitry Kuzmin^{9

10}, Sophie Saboz¹, Josef Mautner¹¹, Jordan Löliger¹, Marco Geigges¹, Darya Palianina¹², Nina Khanna¹², Stefan Dirnhofer¹³, Christian Münz^#², Glenn R Bantug^#¹, Christoph Hess^{1

5}

Collaborators, Affiliations

Collaborators

Swiss Transplant Cohort Study:
Christoph Berger, Christoph Hess, Michael Koller, Simona Rossi, Susanne Stampf, Nicolas J Müller

Affiliations

¹ Immunobiology Laboratory, Department of Biomedicine, University of Basel and University Hospital of Basel, Basel, Switzerland.
² Viral Immunobiology, Institute of Experimental Immunology, University of Zürich, Zürich, Switzerland.
³ Clinical Pharmacology Laboratory, Department of Biomedicine, University of Basel and University Hospital of Basel, Basel, Switzerland.
⁴ Axolabs GmbH, Kulmbach, Germany.
⁵ Cambridge Institute of Therapeutic Immunology and Infectious Disease (CITIID), Department of Medicine, University of Cambridge, Cambridge, UK.
⁶ Bioinformatics Facility, Department of Biomedicine, University Basel and University Hospital of Basel, Basel, Switzerland.
⁷ Experimental Infectious Diseases and Cancer Research, University Children's Hospital of Zürich, Zürich, Switzerland.
⁸ Children's Research Center, University Children's Hospital of Zürich, Zürich, Switzerland.
⁹ Hornet Therapeutics Ltd, London, UK.
¹⁰ Department of Medical Oncology, Yale School of Medicine, New Haven, CT, USA.
¹¹ Department of Gene Vectors, Helmholtz Centre Munich, Munich, Germany.
¹² Laboratory of Infection Biology, Department of Biomedicine, University Basel and University Hospital of Basel, Basel, Switzerland.
¹³ Pathology, Institute of Medical Genetics and Pathology, University Hospital Basel, University of Basel, Basel, Switzerland.

^# Contributed equally.

PMID: 38781354
DOI: 10.1126/science.adk4898

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

Bojana Müller-Durovic et al. Science. 2024.

. 2024 Jul 5;385(6704):eadk4898.

doi: 10.1126/science.adk4898. Epub 2024 Jul 5.

Authors

Collaborators

Swiss Transplant Cohort Study:
Christoph Berger, Christoph Hess, Michael Koller, Simona Rossi, Susanne Stampf, Nicolas J Müller

Affiliations

¹ Immunobiology Laboratory, Department of Biomedicine, University of Basel and University Hospital of Basel, Basel, Switzerland.
² Viral Immunobiology, Institute of Experimental Immunology, University of Zürich, Zürich, Switzerland.
³ Clinical Pharmacology Laboratory, Department of Biomedicine, University of Basel and University Hospital of Basel, Basel, Switzerland.
⁴ Axolabs GmbH, Kulmbach, Germany.
⁵ Cambridge Institute of Therapeutic Immunology and Infectious Disease (CITIID), Department of Medicine, University of Cambridge, Cambridge, UK.
⁶ Bioinformatics Facility, Department of Biomedicine, University Basel and University Hospital of Basel, Basel, Switzerland.
⁷ Experimental Infectious Diseases and Cancer Research, University Children's Hospital of Zürich, Zürich, Switzerland.
⁸ Children's Research Center, University Children's Hospital of Zürich, Zürich, Switzerland.
⁹ Hornet Therapeutics Ltd, London, UK.
¹⁰ Department of Medical Oncology, Yale School of Medicine, New Haven, CT, USA.
¹¹ Department of Gene Vectors, Helmholtz Centre Munich, Munich, Germany.
¹² Laboratory of Infection Biology, Department of Biomedicine, University Basel and University Hospital of Basel, Basel, Switzerland.
¹³ Pathology, Institute of Medical Genetics and Pathology, University Hospital Basel, University of Basel, Basel, Switzerland.

^# Contributed equally.

PMID: 38781354
DOI: 10.1126/science.adk4898

Abstract

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.

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

Collaborators

Affiliations

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

Authors

Collaborators

Affiliations

Abstract

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