A metabolic dependency of EBV can be targeted to hinder B cell transformation.
Bojana Müller-DurovicJessica JägerChristine EngelmannPatrick SchuhmachersSabine AltermattYannick SchlupUrs DuthalerCelia MakowiecGunhild UnterstabSarah RoffeisErta XhafaNadine AssmannFredrik TrulssonRebekah SteinerJoy Edwards-HicksJames WestLorinda TurnerLeyla DeveliogluRobert IvanekTarik AzziPhilippe DehioChristoph Bergernull nullDmitry KuzminSophie SabozJosef MautnerJordan LöligerMarco GeiggesDarya PalianinaNina KhannaStephan DirnhoferChristian MünzGlenn R BantugChristoph HessPublished in: Science (New York, N.Y.) (2024)
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.
Keyphrases
- epstein barr virus
- diffuse large b cell lymphoma
- cell proliferation
- end stage renal disease
- newly diagnosed
- binding protein
- ejection fraction
- climate change
- chronic kidney disease
- adipose tissue
- cell cycle
- prognostic factors
- patient reported outcomes
- peritoneal dialysis
- high fat diet induced
- pi k akt
- monoclonal antibody
- drug induced