Induction of type I interferon by RNA viruses: cellular receptors and their substrates

Baum, Alina; García-Sastre, Adolfo

The search for viral recognition motifs has been a focus of virology research for the past 50 years. With the recent identification of proteins involved in viral recognition, the characteristics of viral motifs that stimulate an antiviral response are now rapidly being discovered. In addition to dsRNA, which has become a paradigm molecule for viral detection, the recent discovery of 5 0 ppp RNA as a possible viral PAMP adds an important piece to this puzzle. Yet, it remains to be shown whether these molecules are indeed physiological triggers of the innate immune system, and if so whether their presence is sufficient for initiation of the antiviral response. It is also important to understand if these RNA molecules are products of viral errors in replication or are an inherent part of the viral life cycle. By convention, virologists have assumed that generation of viral PAMPs is a byproduct of errors in viral replication, and although this type of PAMP generation likely contributes to viral recognition, it is also possible that a component of the virus structure or lifecycle becomes recognized by the cell very early on in viral infection. Indeed, phosphorylation of Ik-B can be observed as early as five minutes after infection of glial cells with measles virus indicating activation of upstream components almost immediately after virus entry (Dhib-Jalbut et al. 1999) . It is always possible that differences in virus preparation, cells, and infection conditions could account for observations which would not be relevant Induction of type I interferon by RNA viruses 1295 to naturally occurring viruses and infections but it is also likely that yet undiscovered sensors or viral PAMPs ensure that infection is recognized immediately in the invaded cell leading to a more rapid innate immune response. Modulation of the innate immune response offers promising and novel approaches for the treatment of infectious agents, cancer, allergies, and autoimmune disorders. Incorporation of TLR and RLR agonists as adjuvants in vaccines is likely to offer significant increase in vaccine potency and efficiency. Currently the only approved TLR agonist is imiquimod (a TLR7 agonist from 3 M Pharmaceuticals) which has been used for treatment of various skin disorders for over 10 years. However, many other TLR agonists are being actively investigated in animal studies and clinical trials (Panter et al. 2009 ). Liposome-nucleic acid complexes which specifically target TLR3, TLR7/8, and TLR9 have also shown to be very effective in treatment of certain cancers and acute viral and bacterial infections (Dow 2008) . Since TLR and RLR signaling often leads to activation of many different cytokines, it is possible that the use of an array of multiple agonists and antagonists could potentially be used to finely regulate the immune response. Moreover, comprehensive screening and evaluation of molecules which act as antagonists of TLRs and RLRs could lead to new insights for the development of potent therapeutics for treatment of autoimmune disorders.