Journal Article

RIG-I Mediates the Co-Induction of Tumor Necrosis Factor and Type I Interferon Elicited by Myxoma Virus in Primary Human Macrophages

Dekaban, Gregory A., Gao, Xiujuan, Wang, Fuan, Rahman, Masmudur, Barrett, John W., McFadden, Grant, Shao, Qing, Mohamed, Mohamed R., Bartee, Eric, Werden, Steve, Irvine, Timothy, Cao, Jingxin

2008

Overview

The sensing of pathogen infection and subsequent triggering of innate immunity are key to controlling zoonotic infections. Myxoma virus (MV) is a cytoplasmic DNA poxvirus that in nature infects only rabbits. Our previous studies have shown that MV infection of primary mouse cells is restricted by virus-induced type I interferon (IFN). However, little is known about the innate sensor(s) involved in activating signaling pathways leading to cellular defense responses in primary human immune cells. Here, we show that the complete restriction of MV infection in the primary human fibroblasts requires both tumor necrosis factor (TNF) and type I IFN. We also demonstrate that MV infection of primary human macrophages (pHMs) activates the cytoplasmic RNA sensor called retinoic acid inducible gene I (RIG-I), which coordinately induces the production of both TNF and type I IFN. Of note, RIG-I sensing of MV infection in pHMs initiates a sustained TNF induction through the sequential involvement of the downstream IFN-regulatory factors 3 and 7 (IRF3 and IRF7). Thus, RIG-I-mediated co-induction of TNF and type I IFN by virus-infected pHMs represents a novel innate defense mechanism to restrict viral infection in human cells. These results also reveal a new regulatory mechanism for TNF induction following viral infection.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Biochemistry/Cell Signaling and Trafficking Structures / Cells, Cultured / DEAD Box Protein 58 / DEAD-box RNA Helicases - biosynthesis / DEAD-box RNA Helicases - genetics / DEAD-box RNA Helicases - metabolism / DNA viruses / Drug Combinations / Fibroblasts - metabolism / Fibroblasts - virology / Gene Expression Regulation, Viral / Gene Silencing / Health aspects / Host-Pathogen Interactions / Humans / Immune system / Immunology/Immunity to Infections / Interferon / Interferon Regulatory Factor-3 - metabolism / Interferon Regulatory Factor-7 - metabolism / Interferon Type I - biosynthesis / Interferon Type I - genetics / Interferon-beta - pharmacology / Interferon-Induced Helicase, IFIH1 / Kinases / Lymphocytes - metabolism / Lymphocytes - virology / Macrophages / Macrophages - metabolism / Macrophages - virology / Medical research / Myxoma virus / Myxoma virus - physiology / Physiological aspects / Poxvirus / Receptors, Immunologic / RNA, Small Interfering - pharmacology / Sensors / Tumor necrosis factor / Tumor Necrosis Factor-alpha - biosynthesis / Tumor Necrosis Factor-alpha - genetics / Tumor Necrosis Factor-alpha - pharmacology / Viral infections / Virology/Host Antiviral Responses / Viruses