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The Role of Suppressor of Cytokine Signaling 1 and 3 in Human Cytomegalovirus Replication

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The Role of Suppressor of Cytokine Signaling 1 and 3 in Human Cytomegalovirus Replication Zurich Open Repository and Archive University of Zurich Main Library Strickhofstrasse 39 CH-8057 Zurich www.zora.uzh.ch Year: 2012 The Role of Suppressor of Cytokine Signaling 1 and 3 in Human Cytomegalovirus Replication Sonzogni, O Posted at the Zurich Open Repository and Archive, University of Zurich ZORA URL: https://doi.org/10.5167/uzh-71661 Dissertation Published Version Originally published at: Sonzogni, O. The Role of Suppressor of Cytokine Signaling 1 and 3 in Human Cytomegalovirus Replica- tion. 2012, University of Zurich, Faculty of Science. The Role of Suppressor of Cytokine Signaling 1 and 3 in Human Cytomegalovirus Replication Dissertation zur Erlangung der naturwissenschaftlichen Doktorwürde (Dr. sc. nat.) vorgelegt der Mathematisch-naturwissenschaftlichen Fakultät der Universität Zürich von Olmo Sonzogni von Moleno, TI Promotionskomitee: Prof. Dr. Nicolas J. Müller (Leitung der Dissertation) Prof. Dr. Christoph Renner (Vorsitz) Prof. Dr. Amedeo Caflisch Zürich, 2012 To my parents Dissertation Table of contents 1. Summary......................................................................................................................9 2. Zusammenfassung ...................................................................................................11 3. Introduction ...............................................................................................................13 3.1 Human cytomegalovirus .........................................................................................13 3.1.1 Epidemiology and clinical relevance..............................................................13 3.1.2 Structure and replication cycle ......................................................................13 3.1.3 Role in allo- and xenotransplantation ............................................................15 3.1.4 The role of the endothelium...........................................................................16 3.1.5 Multifaceted escape mechanisms form host immune defense......................16 3.2 Suppressor of cytokine signaling proteins...........................................................19 3.2.1 The origins.....................................................................................................19 3.2.2 Structure and function ...................................................................................20 3.2.3 SOCS features ..............................................................................................21 3.2.3.1 SOCS1 ........................................................................................................21 3.2.3.2 SOCS3 ........................................................................................................23 3.2.3.3 CIS and SOCS2 ..........................................................................................24 3.2.3.4 Other SOCSs ..............................................................................................24 3.2.4 Role in viral infection .....................................................................................24 3.2.5 Porcine SOCSs .............................................................................................26 3.3 Aim of the study.......................................................................................................27 4. Results part I .............................................................................................................28 4.1 Porcine setting.........................................................................................................29 4.1.1 Detection and modulation of SOCS1 and SOCS3 in HCMV-infected porcine cells ...............................................................................................................29 4.2 Human setting..........................................................................................................32 4.2.1 Upregulation of SOCS1 and SOCS3 in human cells upon stimulation..........32 4.2.2 Detection and modulation of SOCS1 and SOCS3 in HCMV-infected human cells ...............................................................................................................34 4.2.3 Silencing of SOCS1 and SOCS3 in HMVEC leads to impaired HCMV replication ......................................................................................................35 Olmo Sonzogni • July 2012 5 Dissertation 4.2.4 Optimization of the silencing and western blot technique reveal IFN type I activation in silenced HMVEC .......................................................................37 4.2.5 Establishment of a lentiviral transduction system for efficient delivery of short hairpin RNA targeting SOCS1 and SOCS3...................................................39 4.2.6 Silencing of the target protein without Mx induction ......................................42 4.3 Additional material and methods ...........................................................................42 4.3.1 Real Time PCR system for the porcine setting..............................................42 4.3.2 Lentiviral transduction system .......................................................................43 4.3.3 Additional reagents........................................................................................44 5. Results part II ............................................................................................................45 5.1 Abstract ....................................................................................................................47 5.2 Author summary ......................................................................................................48 5.3 Introduction..............................................................................................................49 5.4 Results......................................................................................................................51 5.4.1 Detection and modulation of SOCS1 and SOCS3 in HMVEC.......................51 5.4.2 SOCS1 and SOCS3 are modulated by HCMV infection of HMVEC .............51 5.4.3 Silencing of SOCS3 leads to impaired HCMV replication in HMVEC............52 5.4.4 Silencing of SOCS3 leads to high level of STAT1 and STAT2 phosphorylation in HCMV infected HMVEC.............................................................................52 5.4.5 No differences in type II IFN inducible gene expression between siSOCS3 and siCNTR infected cultures........................................................................53 5.4.6 HCMV needs SOCS3 to control type I IFN inducible gene expression .........53 5.5 Discussion................................................................................................................60 5.6 Materials and methods............................................................................................63 5.6.1 Cells and viruses ...........................................................................................63 5.6.2 Real-Time PCR .............................................................................................64 5.6.3 Western blot ..................................................................................................64 5.6.4 Cells transfection ...........................................................................................65 5.6.5 Cell staining and flow cytometry ....................................................................65 5.6.6 Statistical analysis .........................................................................................66 5.6.7 Author contributions.......................................................................................66 5.6.8 Funding..........................................................................................................66 Olmo Sonzogni • July 2012 6 Dissertation 5.6.9 Competing interests.......................................................................................66 5.6.10 Acknowledgment ...........................................................................................66 6. General discussion...................................................................................................67 6.1 Porcine setting.........................................................................................................67 6.2 Human setting..........................................................................................................68 6.2.1 Detection and induction of SOCS..................................................................68 6.2.2 Silencing of SOCS1 and SOCS3...................................................................70 6.3 Conclusion ...............................................................................................................72 7. References.................................................................................................................73 8. List of abbreviations.................................................................................................88 9. Curriculum vitae........................................................................................................90 10. Acknowledgements ..................................................................................................93 Olmo Sonzogni • July 2012 7 Dissertation 1. Summary Human cytomegalovirus (HCMV) is a large encapsulated virus belonging to the herpesvirus family. Following asymptomatic infection, life-long latency is established in the host and 50-80% of the general
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