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

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

doi:10.1371/journal.ppat.1000099

Abstract

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.

Highlights

Myxoma virus (MV), a member of the poxvirus family, is a large cytoplasmic DNA virus that infects only rabbits [1,2]
We show that the cytoplasmic RNA helicase retinoic acid inducible gene I (RIG-I) is the major sensor that detects invading myxoma virus in primary human macrophages and triggers the co-induction of both tumor necrosis factor and type I interferon
We show that MV infection of primary human macrophages (pHMs) is sensed largely by RIG-I, and the subsequent tumor necrosis factor (TNF) induction is mediated through the sequential involvement of IRF3 and IRF7

Summary

Introduction

Myxoma virus (MV), a member of the poxvirus family, is a large cytoplasmic DNA virus that infects only rabbits [1,2]. No other vertebrate species outside of lagomorphs, including humans, have ever been reported to contract a productive MV infection. This strict host specificity of MV provides an important avenue to study how cross-species virus infections can be manipulated, and how zoonotic infections might be regulated in humans. Disruption of the STAT1 signaling cascade renders normally resistant mice highly susceptible to lethal MV infection [3]. These observations demonstrate the importance of defining the functional antiviral mechanisms in primary cells, as compared to transformed or immortalized cell lines [4]. About the innate defense pathways that inhibit MV infection in normal primary human cells

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Discussion

Conclusion