Evasion of Antiviral Immunity through Sequestering of TBK1/IKKε/ IRF3 into Viral Inclusion Bodies

Cells are equipped with pattern recognition receptors (PRRs) such as the Toll-like and RIG-I-like receptors that mount innate defenses against viruses. However, viruses have evolved multiple strategies to evade or thwart host antiviral responses. Viral in-clusion bodies (IBs), which are accumulated aggregates of viral proteins, are commonly formed during the replication of some viruses in infected cells, but their role in viral immune evasion has rarely been explored. Severe fever with thrombocytopenia syndrome (SFTS) is an emerging febrile illness caused by a novel phlebovirus in the Bunyaviridae. The SFTS viral nonstructural protein NSs can suppress host beta interferon (IFN-) responses. NSs can form IBs in infected and transfected cells. Through interaction with tank-binding kinase 1 (TBK1), viral NSs was able to sequester the IKK complex, including IKK and IRF3, into IBs, although NSs did not interact with IKK or IRF3 directly. When cells were infected with influenza A virus, IRF3 was phos-phorylated and active phosphorylated IRF3 (p-IRF3) was translocated into the nucleus. In the presence of NSs, IRF3 could still be phosphorylated, but p-IRF3 was trapped in cytoplasmic IBs, resulting in reduced IFN- induction and enhanced viral replica-tion. Sequestration of the IKK complex and active IRF3 into viral IBs through the interaction of NSs and TBK1 is a novel mecha-nism for viral evasion of innate immunity. Viruses have adopted various mechanisms to evade or subverthost antiviral responses initiated by viral RNA or DNA through Toll-like receptor (TLR) (1, 2) and RIG-I-like receptor (RLR) (3–5) signaling pathways. Viral double-stranded RN