Virus-cell fusion as a trigger of innate immunity dependent on the adaptor STING

 Holm et al. 2012. Nat. Immunol. 13(8):737-743

Speaker: Wei-Hung Lin (林韋宏)                                 Time: 13:00~14:00, Sep. 26, 2012

Commentator: Pin Ling, Ph.D. (凌斌)                          Place: Room 601

Abstract

The innate immune system senses pathogen infection by using pattern recognition receptors (PRRs) that detect pathogen-associated molecular patterns (PAMPs). Viral nucleic acids are the typical PAMPs that are recognized by some PRRs including Toll-like receptors (TLRs) and RIG-I-like receptors, which induce cellular gene expression involved in interferon and inflammation responses1,2. In this study, Holm et al. reveal a novel mechanism that the innate immune system senses virus infection independently of viral DNA or RNA. They show that herpes simplex virus-derived virus-like particles (VLPs) lacking viral capsids and nucleic acids are still able to induce typeⅠinterferon and interferon-stimulated genes. This interferon response cannot be induced when the HSV fusogenic proteins are mutated, suggesting that membrane fusion between VLPs and cells are required therein. Furthermore, the authors demonstrate that membrane fusion-induced interferon response is not restricted to infectious contexts because cell-cell fusion and liposome-cell fusion can also induce the response. While the response is independent of TLRs and their downstream adaptor proteins, it requires a signaling adaptor STING, TBK1 and IRF3. Meanwhile, phospholipase C-g and phosphatidylinositol-3-OH kinase are involved in its membrane-proximal signaling event. Notably, the innate response to membrane fusion is restricted to the typeⅠinterferon response but has no apparent effect on proinflammatory cytokine expression, inflammasome activation and autophagy. However, the VLP-cell fusion induces recruitment and activation of leukocytes in vivo and synergistically enhances responses of TLR7 and TLR9 to their ligands, suggesting that membrane fusion serves as an early danger signal that facilitates or optimizes the innate immune response to viral infection.

References

1.      Paludan, S.R., Bowie, A.G., Horan, K.A. & Fitzgerald, K.A. Recognition of herpesviruses by the innate immune system. Nat. Rev. Immunol. 11, 143–154 (2011).

2.      Brennan, K. & Bowie, A.G. Activation of host pattern recognition receptors by viruses. Curr. Opin. Microbiol. 13, 503–507 (2010).