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

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. [Display omitted] [Display omitted] •Chronic viral infection causes long-term transcriptome and proteome changes in the liver•Hepatocyte-intrinsic type I interferon (IFN-I) signaling regulates hepatic metabolism•IFN-I signaling reprograms the urea cycle in hepatocytes and alters serum metabolites•Serum levels of arginine and ornithine modulate T cell responses and pathology The liver is a central regulator of metabolism, but how infection-induced changes in liver metabolism affect immune responses and pathology remains enigmatic. Lercher et al. demonstrate that hepatocyte-intrinsic type I interferon (IFN-I) represses metabolism during chronic viral infection. Specifically, IFN-I disrupts the urea cycle in hepatocytes, altering serum arginine and ornithine levels, which dampen antiviral T cells responses and liver pathology.