RIG-I mediates the co-induction of tumor necrosis factor and type I interferon elicited by myxoma virus in primary human macrophages

被引:77
作者
Wang, Fuan [1 ,2 ]
Gao, Xiujuan [1 ,2 ]
Barrett, John W. [1 ,2 ]
Shao, Qing [3 ]
Bartee, Eric [4 ]
Mohamed, Mohamed R. [4 ]
Rahman, Masmudur [4 ]
Werden, Steve [4 ]
Irvine, Timothy [1 ,2 ]
Cao, Jingxin [5 ]
Dekaban, Gregory A. [1 ,2 ]
McFadden, Grant [1 ,2 ,4 ]
机构
[1] Robarts Res Inst, Biotherapeut Res Grp, London, ON N6A 5C1, Canada
[2] Univ Western Ontario, Dept Microbiol & Immunol, London, ON, Canada
[3] Univ Western Ontario, Dept Anat & Cell Biol, London, ON, Canada
[4] Univ Florida, Coll Med, Dept Mol Genet & Microbiol, Gainesville, FL USA
[5] Publ Hlth Agcy Canada, Natl Microbiol Lab, Winnipeg, MB, Canada
基金
加拿大健康研究院;
关键词
D O I
10.1371/journal.ppat.1000099
中图分类号
Q93 [微生物学];
学科分类号
071005 ; 100705 ;
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.
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页数:13
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