The small basic C protein is a virulence factor that contributes to innate immunity evasion of Paramyxoviridae, but its mechanisms of action are incompletely understood. Focusing on the measles virus (MeV) C protein, we have shown that, first, it promotes accurate RNA synthesis by limiting the production of defective-interfering (DI) RNA. Second, we show here that C is recruited to sites of replication only when the large (L) subunit of the viral polymerase is present, suggesting the possibility of direct L-C protein interactions. We seek now to characterize the mechanisms of C protein action. The central hypothesis is that it is a co-factor that regulates RNA synthesis and enhances polymerase accuracy, thereby limiting the generation of DI RNA and the activation of innate immunity.
The specific aims are, first, to assess how C interacts with L to promote polymerase accuracy. Second, to characterize how the C protein regulates viral genome replication and transcription. Third, to assess whether transcripts produced by copy-back DI RNAs are the main activator of the interferon response.
Although targeted for eradication, measles remains the most transmissible human respiratory infection, and as such a substantial public health issue. Here we seek to better characterize mechanisms that enhance the accuracy of measles virus replication, facilitating innate immune evasion. Our results may serve as paradigm for similar analyses of related viruses. In addition, measles and other negative strand viruses are currently being developed as oncolytic vectors that selectively eliminate cancer cells. Knowledge of the basic mechanisms of virus spread is fundamental for the development of safe and effective oncolytic vectors.
|Ma, Dzwokai; George, Cyril X; Nomburg, Jason et al. (2017) Upon Infection the Cellular WD Repeat-containing Protein 5 (WDR5) Localizes to Cytoplasmic Inclusion Bodies and Enhances Measles Virus Replication. J Virol :|