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

PLoS Pathogens

John W. Barrett¹  Eric Bartee¹  Fuan Wang¹  Grant McFadden¹  Masmudur Rahman²  Xiujuan Gao³  Mohamed R. Mohamed³  Qing Shao³  Steve Werden⁴  Jingxin Cao⁴  Gregory A. Dekaban⁴  Timothy Irvine⁴ 

[1] BioTherapeutics Research Group, Robarts Research Institute, London, Ontario, Canada;Department of Anatomy & Cell Biology, The University of Western Ontario, London, Ontario, Canada;Department of Microbiology and Immunology, The University of Western Ontario, London, Ontario, Canada;Department of Molecular Genetics and Microbiology, College of Medicine, University of Florida, Gainesville, Florida, United States of America

关键词: Small interfering RNAs;    Fibroblasts;    Cytokines;    Enzyme-linked immunoassays;    Macrophages;    Antibodies;    Messenger RNA;    Reverse transcriptase-polymerase chain reaction;   

DOI  :  10.1371/journal.ppat.1000099

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY