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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AI128037-02
Application #
9406235
Study Section
Virology - A Study Section (VIRA)
Program Officer
Park, Eun-Chung
Project Start
2017-01-01
Project End
2018-12-31
Budget Start
2018-01-01
Budget End
2018-12-31
Support Year
2
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905