Research Highlights : Medicine , Biology
Missing link in antiviral immune response revealed
29 June 2006 (Volume 1 Issue 6)
Deciphering of a key step in a biochemical pathway is a mighty leap forward in understanding how mammalian immune systems work.
Missing link in antiviral immune response revealedenlarge image
Immunologists at RIKEN have characterized a key component of the biochemical chain of events that leads to the release of interferon- α, an antiviral factor, following detection of viruses by specialized sensors expressed on the surface of dendritic cells, a kind of immune cell.
Humans and other animals are born with a sophisticated defence mechanism against viral and other microbial invasions. This so called 'innate immune response' consists of first detecting an invading particle via specific, preprogrammed sensors, also called 'receptors', followed by transmission of the signal through a unique intracellular signalling pathway, a 'signalling cascade', which leads to a 'first line of defence' immune response such as the release of interferon-α.
Tsuneyasu Kaisho from RIKEN's Research Center for Allergy and Immunology in Yokohama and colleagues from the University of Tokushima, the Research Institute for Microbial Diseases and ERATO in Osaka and Kazusa DNA Research Institute in Kisarazu, Japan, have worked out the key molecular step that mediates interferon induction by two members of the Toll-like receptor (TLR) family, TLR7 and TLR9. These receptors specialize on detecting singlestranded RNA and DNA viruses such as the influenza virus and herpes virus, respectively.
Previously, researchers had described the different components of the signalling cascade triggered by TLR7 and TLR9. It consists of an 'adaptor', MyD88, which transmits the signal detected by the receptors to an interferon'regulatory factor', IRF7, which in turn is responsible for activating the interferon response1,2. How exactly the signal is transmitted from MyD88 to IRF7 remained a mystery, however.
As reported recently in Nature3, Kaisho and colleagues have now determined that a kinase, IκB kinase-α, an enzyme that could potentially activate IRF7 by chemically attaching a phosphate group to it, is the key player in this step. In a series of experiments with human kidney cells, the RIKEN authors first show that IRF7 is indeed modified by IκB kinase- α. They then proceed to demonstrate that an inactivated version of the kinase inhibits MyD88-induced interferon- α production. Finally, they prove that in mice lacking IκB kinase- α, interferon- α production is greatly reduced.
The mechanistic insights gained by Kaisho and colleagues could aid the design of drugs that activate or block the TLR7- and TLR9-induced interferon- α pathway. This would be useful in the treatment of viral infections where interferon-α serves as an antidote. In addition, the treatment of autoimmune diseases such as lupus, in which the interferon response is constantly activated, could benefit from drugs that reduce IκB kinase-α activity.
- Kawai, T. et al., Interferon-induction through Toll-like receptors involves a direct interaction of IRF-7 with MyD88 and TRAF6. Nat. Immunol. 5(10): 1061・068 (2004). | article |
- Honda, K. et al., IRF-7 is the master regulator of type-I interferon-dependent immune responses. Nature 434: 772・77 (2005). | article |
- Hoshino, K. et al. IkB kinase- is critical for interferon- production induced by Toll-like receptors 7 and 9. Nature 440: 949・53 (2006). | article |