ESR 15 - Elucidation of herpesvirus evasion mechanisms through CRISPR/Cas-mediated engineering of virus and host genes

University Medical Center Utrecht, The Netherlands

 

 

Student: Patrique Praest, Ph.D. fellow

Supervisor: Prof. Emmanuel J.H.J. Wiertz, D.V.M., Ph.D.

Co-supervisor: Assistant Prof. Robert Jan Lebbink, Ph.D.

 

 

Several hundred million years of co-evolution between vertebrates and invading pathogens have shaped the adaptive immune system of the hosts to fight back the unwanted invaders through highly developed defense mechanisms. Herpesviruses manage to dodge this immune response by interfering with one of the central hinges of human adaptive immunity, the major histocompatibility complex (MHC) class I antigen presentation pathway. This pathway is responsible for the presentation of pathogen-derived peptide fragments to patrolling cytotoxic T-cells; upon recognition of a virus-encoded peptide, the cytotoxic T-cells will induce cell death of the infected cell. One of the bottlenecks of this pathway is the loading of peptides onto MHC-I molecules in the endoplasmic reticulum (ER). This task is accomplished by the MHC class I peptide-loading complex (PLC), of which the transporter associated with antigen-processing (TAP) is a key component. Due to its central role it is not surprising that TAP is a highly sought-after target for viral inhibition mechanisms, especially among viruses such as herpesviruses that develop life-long infections.

 

In this project, we aim for a better understanding of the multiple ways herpesviruses evade recognition of the immune system. The focus lies on herpesvirus-encoded TAP inhibitors; four TAP-inhibiting proteins have been identified in herpesviruses so far. To study their function, we want to make use of the CRISPR/Cas-system to knock out specific viral or host genes. Furthermore, new techniques like Cryo-electron-microscopy could give us new insights into structural details of TAP-inhibition by herpesviruses.

 

The ultimate goal of this study is to provide information that will aid the discovery of new antiviral therapies.

 

 


 

Contact details

Emmanuel J.H.J. Wiertz, Professor of Medical Microbiology / Experimental Virology

Department of Medical Microbiology

University Medical Center Utrecht

G04.647

Heidelberglaan 100

3584 CX Utrecht

The Netherlands

This email address is being protected from spambots. You need JavaScript enabled to view it.

 

 

Assistant Prof. Robert Jan Lebbink

Department of Medical Microbiology

University Medical Center Utrecht

G04.522

Heidelberglaan 100

3584 CX Utrecht

The Netherlands

Phone: +31 887 55 0627

This email address is being protected from spambots. You need JavaScript enabled to view it.