Type I Interferon Signaling Disrupts the Hepatic Urea Cycle and Alters Systemic Metabolism to Suppress T Cell Function

Alexander Lercher,Anna Orlova,Daniela Reil,Hatoon Baazim,Jörg Menche,Theresa Pinter,Burkhard Ludewig,Keiryn L Bennett,Richard Moriggl,Michael Caldera,Lindsay Kosack,Gernot Schabbauer,Ulrich Kalinke,Jakob-Wendelin Genger,Kristaps Klavins,Moritz F Schlapansky,Natalia Pikor,Anannya Bhattacharya,Benedikt Agerer,Dijana Vitko,Michael Trauner,Bettina Gürtl,Peter Marynen ,Paul Cheng ,Mária Ozsvár-Kozma ,Alexandra Popa ,Julia Brunner ,Andréas Bergthaler

doi:10.1016/j.immuni.2019.10.014

Abstract

Infections induce complex host responses linked to antiviral defense, inflammation, and tissue damage and repair. We hypothesized that the liver, as a central metabolic hub, may orchestrate systemic metabolic changes during infection. We infected mice with chronic lymphocytic choriomeningitis virus (LCMV), performed RNA sequencing and proteomics of liver tissue, and integrated these data with serum metabolomics at different infection phases. Widespread reprogramming of liver metabolism occurred early after infection, correlating with type I interferon (IFN-I) responses. Viral infection induced metabolic alterations of the liver that depended on the interferon alpha/beta receptor (IFNAR1). Hepatocyte-intrinsic IFNAR1 repressed the transcription of metabolic genes, including Otc and Ass1, which encode urea cycle enzymes. This led to decreased arginine and increased ornithine concentrations in the circulation, resulting in suppressed virus-specific CD8+ T cell responses and ameliorated liver pathology. These findings establish IFN-I-induced modulation of hepatic metabolism and the urea cycle as an endogenous mechanism of immunoregulation.Video

Highlights

Differentially expressed genes associated with antiviral IFN-I signaling were found to be enriched on day 2 leukocyte-associated genes were mainly found on day 8 after infection
In a more stringent analysis using the limma (2 3 2 factorial) interaction model, we found 15 serum metabolites to be regulated by hepatocyte-intrinsic IFNAR1 signaling, including the semi-essential amino acid arginine and its downstream metabolite ornithine (Figure 3F)
Our study identified an IFNAR1-dependent mechanism whereby hepatocytes receive instructions to repress the transcription of genes with metabolic function