Primary Supervisor: Prof. Marit W. Anthonsen, Norwegian University of Science and Technology, Trondheim, Norway
Title: Unraveling changes in metabolic pathways associated with type III IFN-mediated signalling by pneumoviruses
Collaborators: Prof. F. van Kuppeveld, University Utrecht, The Netherlands; Dr. N. Manel, Stimunity, Paris, France
Early Stage Researcher: Alix Spahn
PROJECT DESCRIPTION
Type III IFNs have been identified as a new class of cytokines that are specialized towards virus defense at mucosal surfaces. Although recent evidence suggests that antiviral responses are supported by IFN-induced rewiring of the cellular metabolism, the involvement of metabolic reprogramming to type III IFN induction as well as the metabolic changes elicited by type III IFNs are largely unknown. RNA viruses, such as the pneumoviruses respiratory syncytial virus and human metapneumovirus, are sensed through cytoplasmic RIG-I-like receptors engaging the adaptor protein MAVS on mitochondria or peroxisomes, thereby inducing IFN production and antiviral responses. The transcription factor IRF1 (interferon regulatory factor 1) has been proposed to exert a specific role in peroxisomal signaling and induction of type III IFNs. The aim of this project is to define metabolic changes implicated in the MAVS-IRF1-type-III IFN axis in pneumovirus-infected cells. The ESR will apply RNA sequencing and Seahorse technology to determine metabolic genes and characteristics of glycolysis and oxidative phosphorylation in pneumovirus-infected human cells. Chemical inhibitors, RNA interference or CRISPR/Cas technology will be used to target components of metabolic pathways to assess their contribution to IRF1-mediated type III IFN production and viral replication. Metabolic changes induced by type III IFNs will be explored using recombinant type III IFN and modulators of the type III IFN receptor. Subcellular events involved in peroxisome/mitochondria/organelle-specific signaling will be determined in collaboration with prof. F. van Kuppeveld, University of Utrecht. The innate immune adaptor STING contributes to RNA virus infections and has been shown to link metabolism and immune responses. In collaboration with Dr. N. Manel at Stimunity, Paris, the impact of STING-signaling to immunometabolic changes in response to pneumoviruses will be determined. Overall, the project will shed light on metabolic regulators implicated in type III IFN responses and establish their impact on pneumovirus replication.
