RIP3 is involved in host defense against HSV-1 infection via enhancing STING mediated antiviral signaling (P1405)

Abstract

Abstract Herpes simplex virus type 1 (HSV-1), a double stranded DNA virus, is a widespread virus that infects approximately 80% of adults worldwide. HSV-1 infection is also the major cause of fatal childhood HSV-1 encephalitis (HSE). The mechanisms of how host cells defend against HSV-1 are still not fully known. Here we report that receptor interacting protein 3 (RIP3) enhances type I interferon production in response to HSV-1 infection. In our study of the functions of RIP3, we have found that the HSV-1 replication in RIP3 knockout L929 was unrestrained, and that HSV-1 induced TBK1 and IRF3 activations were impaired in RIP3 deficient cells. Further study has shown that over-expression of wild type RIP3, but not RHIM-mutant RIP3, enhances type I interferon production, especially when co-expressed with STING, a central signaling molecule in the innate immune response to DNA virus infection. Upon treating the cell with HSV-1, TBK1 was recruited to RIP3. In addition, RIP3 can promote the interaction between STING and TBK1 in a RHIM dependent manner. We propose that upon HSV-1 stimulation, RIP3 promotes the recruitment of TBK1 to STING, which leads to TBK1-mediated IRF3 activation and subsequent type I IFN secretion. Our study revealed that, in addition to its function in necrosis, RIP3 plays a role in type I interferon production. These results may also provide a new perspective for the exploration of childhood HSE pathogenesis.