Unravelling the interactions between poxviruses and their host

Luteijn, Rutger

Promoter:
Prof.dr. E.J.H.J. (Emmanuel) Wiertz
Co-promoter:
Dr. M.E. (Maaike) Ressing & dr. R.J. (Robert-Jan) Lebbink
Research group:
Lebbink , Wiertz
Date:
October 27, 2016
Time:
10:30 h

Summary

During my PhD research, we have discovered novel interactions between poxviruses and their host. We have elucidated the role of these interactions on virus infection and evasion of the host immune system. We identified the mechanism by which the cowpox virus protein CPXV012 eludes the adaptive immune response. We showed that CPXV012 inhibits ATP binding to the transporter associated with antigen processing (TAP). Thereby, CPXV012 blocked proper loading of antigens on MHC I molecules and subsequent antigen presentation to T cells. Furthermore, we used the CRISPR/Cas9 system to study mutagenic repair of poxvirus genomes. We adjusted this system for the rapid generation of defined poxvirus mutants. We showed that poxvirus DNA repair in the cytosol is critically dependent on nuclear DNA repair pathways, including host cell DNA ligase IV.

Finally, we performed a genome-wide haploid genetic screen to identify novel host factors involved in vaccinia virus infection. We revealed the role of several host factors in virus infection, and identified novel players in important biological processes, including heparan sulfate expression, and actin cytoskeleton remodeling. 

In conclusion, we unravelled important novel poxvirus-host cell interactions. Revealing these interactions not only contributed to our knowledge of this important pathogen, they also significantly aided in unravelling fundamental biological processes. These advances may ultimately lead to new druggable targets and therapies for a wide variety of diseases.