Infection of B cells by Epstein Barr virus (EBV) leads to proliferation and transformation of these cells via the EBV protein EBNA2 that may contribute to immune dysregulation and lymphomagenesis. In Science, Müller-Durovic et al. identify a druggable virus-driven metabolic pathway that is required for latent transformation of B cells. Monitoring the metabolic and transcriptional responses to early EBV infection, the authors found that EBV-infected B cells engage in de novo biosynthesis of NAD. By blocking activity of the metabolic enzyme IDO1 using inhibitors or short interfering RNA (siRNA) and performing metabolic tracing with U-13C-tryptophan and metabolite addback experiments, they show that IDO1 activity is required for transformation of EBV-infected cells. Chromatin immunoprecipitation (ChIP) experiments in an EBNA2-deleted EBV strain showed that EBNA2 regulates IDO1 expression via EBF1. The authors confirm their results in vivo using a mouse model with adoptively transferred B cells infected with either wild-type EBV or the EBNA2-deleted EBV strain, and in a humanized mouse model. Analysis of the infected B cell transcriptome and metabolic flux experiments demonstrate that the IDO1–NAD axis enables the production of mitochondrial ATP required for proliferation and transformation. Using the prospective Swiss Transplant Cohort Study (STCS) to assess IDO1 expression in EBV-positive patients, the authors find associative evidence for a role for EBV-driven IDO1 activity in lymphomagenesis in recipients of solid organ transplants. The treatment of humanized mice with IDO1 inhibitors reduced EBV-driven lymphomagenesis and viral loads. This research suggests a possible immunometabolic intervention to restrict the development of latent EBV infection and reduce EBV-driven lymphomageneis.
Original reference: Science https://doi.org/10.1126/science.adk4898 (2024)
This is a preview of subscription content, access via your institution
