Research on molecular mechanisms of double stranded DNA-mediated innate immune activation

点击翻译按钮获取中文摘要

Research has been conducted 1)to identify molecules involved in innate immune activation mediated by double stranded DNA and 2)to analyze their roles in gene-mediated vaccines and gene therapies. By screening of a cDNA expression library, it was revealed that histone H2B, a component of the core histone complex, is involved in dsDNA (B-DNA)-mediated type I interferon (IFN) production pathway. We further examined about a role of histone H2B in innate immune responses by using RNA interference (siRNA) and found that nock-down of histone H2B led to suppression of type I IFN production induced by B-DNA. Moreover, knock-down of histone H2B resulted in elevation of replication efficiency of DNA viruses such as adenovirus, herpes simplex virus, and human papilloma virus, while it had little impact on replication of RNA viruses such as vesicular stomatitis virus and encephalomycarditis virus. These results suggested that histone H2B plays a significant role in recognition of viral DNA and initiation of innate immune responses to suppress viral replication. CIAO (C-terminal importin9-associated molecule organizing histone H2B and IPS-1) was identified after screening of histone H2B interacting molecules by using a yeast two hybrid system. It was shown that CIAO interacts with both histone H2B and IPS-1 and plays a critical role in IPS-1-mediated type I IFN production. Finally, it was demonstrated that the immunogenicity of DNA vaccine is critically controlled by an IRF kinase, TBK1, which is essential for histone H2B-mediated signaling by using TBK1 KO mice.