Modulation of the Innate Immune Response to Measles Virus Infection by PKR and ADAR1

• Applicant: Dr. Christian Pfaller
• Subject Area: Virology
• Term: from 2012 to 2014
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 221802653

The protein kinase R (PKR) and the adenosine deaminase acting on RNA 1 (ADAR1) are both enzymes activated upon binding to double-stranded RNA (dsRNA). Both proteins are interferon-stimulated genes (ISGs) and play important roles in the innate antiviral response. Activation of PKR leads to a general translational shutdown. ADAR1 deaminates adenosines (A) on the bound dsRNA, which gives rise to inosine (I) and results (a) in the destabilization of dsRNA structures; and (b) introduction of mutations into the target RNA, since I is recognized as G instead of A. Previous studies have shown that both PKR and ADAR1 modulate the signaling processes leading to the production of interferon and ISGs.Measles virus (MV) is a negative ssRNA virus and member of the family of Paramyxoviridae. In case of MV, PKR clearly acts antiviral, while ADAR1 is proviral. Although the contribution of PKR and ADAR1 to innate immune signaling have been described in the past, still it is unclear why the enzymes get activated by a ssRNA virus like MV.One goal of this project is to clarify the mechanisms behind the apparently opposed functions of PKR and ADAR1 during MV infection.A second goal is to shed light on the RNAs that are recognized by PKR and ADAR1 thereby activating the proteins. We will purify RNA-protein complexes with PKR and ADAR1 and characterize the purified RNAs on a molecular level, which will give rise to a new class of pathogen-associated molecular patterns (PAMPs) during MV infection which have not been considered carefully so far. Thirdly, we will investigate the function of the viral C protein, which has been shown to be a crucial factor to prevent the production of PKR- and ADAR1-activating PAMPs during MV infection.The aim of this project is to gain deeper insights into the molecular biology of MV and its interplay with the immune response, which is immensely important for the generation of multivalent vaccines and vectored MVs used in oncolytic virotherapy.

• DFG Programme: Research Fellowships
• International Connection: USA
• Hosts: Professor Roberto Cattaneo, Ph.D.; Professor Charles E. Samuel