Modeling infection and antiviral therapy of enteric viruses using primary intestinal organoids

252 Pages·2017·13.27 MB·English

by  Y. Yin

Modeling infection and antiviral therapy of
enteric viruses using primary intestinal
organoids

Yuebang Yin
The studies presented in this thesis were performed at the Laboratory of
Gastroenterology and Hepatology, Erasmus MC-University Medical Center
Rotterdam, the Netherlands.

The research was funded by:
 Netherlands Organization for Scientific Research (NWO);
 Dutch Digestive Foundation (MLDS);
 Daniel den Hoed Foundation.

Financial support for printing of this thesis was provided by:
Erasmus Postgraduate School Molecular Medicine

© Copyright by Yuebang Yin. All rights reserved.
No part of the thesis may be reproduced or transmitted, in any form, by any means,
without express written permission of the author.

Cover design and layout: Yuebang Yin

Printed by: RIDDERPRINT

ISBN: 978-94-6299-622-9
Modeling infection and antiviral therapy of
enteric viruses using primary intestinal
organoids

Modeleren van infectie en antivirale therapie van enterische virussen met
primaire intestinale organoiden

Thesis
to obtain the degree of Doctor from the
Erasmus University Rotterdam
by command of the
rector magnificus
Prof.dr. H.A.P. Pols
and in accordance with the decision of the Doctorate Board
The public defense shall be held on

Tuesday 27th June 2017 at 11:30 AM

by
Yuebang Yin

born in Shangqiu City, Henan province, China
Doctoral Committee
Promoter:
Prof.dr. M. P. Peppelenbosch

Inner Committee:
Prof.dr. C.J. van der Woude
Prof.dr. J.C.H. Hardwick
Dr. M. Spaargaren

Copromoter:
Dr. Q. Pan
Cover:

The picture on the cover is designed by the author based on an image in the thesis.

Table of Contents
Chapter 1 General introduction and outline of the thesis 1

Chapter 2 Rotavirus in organ transplantation: drug-virus-host
interactions 19

Chapter 3 Modeling rotavirus infection and antiviral therapy using
primary intestinal organoids 39

Chapter 4 Mycophenolic Acid Potently Inhibits Rotavirus Infection with
a High Barrier to Resistance Development 71

Chapter 5 6-thioguanine potently inhibits rotavirus infection through
suppression of Rac1 activation 99

Chapter 6 PI3K-Akt-mTOR-4E-BP1 axis sustains rotavirus infection
via the 4E-BP1 mediated autophagy pathway and
represents an antiviral target 127

Chapter 7 The eukaryotic translation initiation factor 4F complex
inhibits rotavirus infection 167

Chapter 8 Inhibition of calcineurin or IMPDH exerts moderate to
potent antiviral activity against norovirus replication 185

Chapter 9 Summary and general discussion 219

Chapter 10 Appendix 231
Dutch Summary 233
Curriculum vitae 236
PhD Portfolio 237
Acknowledgements 239
List of Publications 243

CHAPTER 1

General introduction and outline of the thesis

1 | P age
2 | P age