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Immunity. 2019 Nov 26. pii: S1074-7613(19)30458-3. doi: 10.1016/j.immuni.2019.10.014. [Epub ahead of print]

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

Author information

1
CeMM Research Center for Molecular Medicine or the Austrian Academy of Sciences, Lazarettgasse 14 AKH BT25.3, 1090 Vienna, Austria.
2
Department of Thrombosis Research and Vascular Biology, Medical University of Vienna, 1090 Vienna, Austria; Christian Doppler Laboratory for Arginine Metabolism in Rheumatoid Arthritis and Multiple Sclerosis, 1090 Vienna, Austria.
3
CeMM Research Center for Molecular Medicine or the Austrian Academy of Sciences, Lazarettgasse 14 AKH BT25.3, 1090 Vienna, Austria; Department of Urology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
4
CeMM Research Center for Molecular Medicine or the Austrian Academy of Sciences, Lazarettgasse 14 AKH BT25.3, 1090 Vienna, Austria; Research Institute of Molecular Pathology (IMP), Vienna BioCenter (VBC), 1030 Vienna, Austria.
5
Institute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna, 1210 Vienna, Austria.
6
Institute of Immunobiology, Kantonsspital St. Gallen, 9007 St. Gallen, Switzerland.
7
CeMM Research Center for Molecular Medicine or the Austrian Academy of Sciences, Lazarettgasse 14 AKH BT25.3, 1090 Vienna, Austria; Department for Laboratory Medicine, Medical University of Vienna, 1090 Vienna, Austria.
8
Institute for Experimental Infection Research, TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Helmholtz Centre for Infection Research, Braunschweig, and the Hannover Medical School, 30625 Hannover, Germany.
9
Institute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna, 1210 Vienna, Austria; Medical University of Vienna, 1090 Vienna, Austria.
10
Bio-Cancer Treatment International Limited, Hong Kong, China.
11
Division of Gastroenterology & Hepatology, Department of Internal Medicine III, Medical University of Vienna, 1090 Vienna, Austria.
12
CeMM Research Center for Molecular Medicine or the Austrian Academy of Sciences, Lazarettgasse 14 AKH BT25.3, 1090 Vienna, Austria. Electronic address: abergthaler@cemm.oeaw.ac.at.

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 ABSTRACT.

KEYWORDS:

CD8 T cells; hepatitis; hepatocyte; immunometabolism; infection; inflammation; interferons; liver; urea cycle; virus

PMID:
31784108
DOI:
10.1016/j.immuni.2019.10.014
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