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

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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. Myxoma virus, a member of the cytoplasmic DNA poxvirus family, causes a lethal disease called myxomatosis in the European rabbit. It has been known for over a half-century that other vertebrates, including humans, are highly resistant to myxoma virus infection, even following direct injections of live myxoma virus. Interestingly, myxoma virus has been recently shown to potently infect and kill malignant human tumors xenografted in mice. However, little is known about how normal human immune cells sense and suppress myxoma virus multiplication at the cellular level. Here, we show that the cytoplasmic RNA helicase 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. Together, tumor necrosis factor and type I interferon inhibit myxoma virus in otherwise permissive cells, such as human fibroblasts. Conceptually, our study thus demonstrates that intracellular RNA sensors may, in general, play a more important role than previously thought in the innate antiviral responses against DNA virus infections in human cells.