奥地利科学院Andreas Bergthaler团队近期研究发现，1型干扰素信号通过干扰肝尿素循环并改变全身代谢来抑制T细胞功能。相关论文2019年11月26日在线发表于《免疫》。

研究人员认为肝脏作为中心代谢枢纽，可能在感染过程中协调全身性代谢变化。研究人员用慢性淋巴细胞性脉络丛脑膜炎病毒（LCMV）感染了小鼠，进行了肝组织的RNA测序和蛋白质组学，并将这些数据与不同感染阶段的血清代谢组学进行了整合。感染后早期发生肝脏代谢的广泛重编程，与I型干扰素（IFN-I）反应相关。病毒感染引起肝脏的代谢改变，这取决于干扰素α/β受体（IFNAR1）。肝细胞固有的IFNAR1抑制了包括Otc和Ass1在内的代谢基因的转录，这些基因编码尿素循环酶。这导致精氨酸减少和循环中鸟氨酸浓度增加，从而使得病毒特异性CD8阳性T细胞反应受到抑制，肝脏病理得到改善。这些发现表明IFN-I诱导的肝代谢和尿素循环调节可作为免疫调节的内源性机制。

据悉，感染引起复杂的宿主反应，这些反应与抗病毒防御、炎症、组织损伤和修复有关。

附：英文原文

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

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

Issue&Volume: November 26, 2019

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.

DOI: 10.1016/j.immuni.2019.10.014

Source: https://www.cell.com/immunity/fulltext/S1074-7613(19)30458-3