Molecular mechanisms of dengue virus infection Flipse, Jacobus

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1 Molecular mechanisms of dengue virus infection Flipse, Jacobus IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from it. Please check the document version below. Document Version Publisher's PDF, also known as Version of record Publication date: 2015 Link to publication in University of Groningen/UMCG research database Citation for published version (APA): Flipse, J. (2015). Molecular mechanisms of dengue virus infection: cell tropism, antibody-dependent enhancement, and cytokines [Groningen]: University of Groningen Copyright Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons). Take-down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. Downloaded from the University of Groningen/UMCG research database (Pure): For technical reasons the number of authors shown on this cover page is limited to 10 maximum. Download date:

2 Molecular Mechanisms of Dengue Virus Infection Cell Tropism, Antibody-Dependent Enhancement, and Cytokines Jacobus Cornelis (Jacky) Flipse

3 The work presented in this thesis has been performed within the University of Groningen, University Medical Center Groningen, Department of Medical Microbiology, Groningen, the Netherlands. This work was funded through an ALW-VIDI grant to J.M. Smit, and supported by the Jan Kornelis de Kock foundation (Groningen) and Immunotools GmbH (Germany). Financial support for printing this thesis was kindly provided by: the University of Groningen, the Graduate School of Medical Sciences, Nederlandse Vereniging voor Medische Microbiologie / Koninklijke Nederlandse Vereniging voor Microbiologie (NVMM/KNVM), Koninklijk Zeeuwsch Genootschap der Wetenschappen, and Greiner Bio-One. Molecular Mechanisms of Dengue Virus Infection Cell Tropism, Antibody-Dependent Enhancement, and Cytokines Proefschrift Molecular Mechanisms of Dengue Virus Infection Dissertation of the University of Groningen ISBN: (printed version) ISBN: (electronic version) Copyright 2015 Jacky Flipse Cover idea and design: Jacky Flipse Printed by: Ridderprint BV Layout: Ridderprint BV All rights reserved. No parts of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, without the written permission of the author. The copyright of previously published chapters of this thesis also remains with the publisher or journal. ter verkrijging van de graad van doctor aan de Rijksuniversiteit Groningen op gezag van de rector magnificus prof. dr. E. Sterken en volgens besluit van het College voor Promoties. De openbare verdediging zal plaatsvinden op 26 oktober 2015 om 12:45 uur door Jacobus Cornelis Flipse geboren op 27 februari 1986 te Goes

4 Promotor Prof. dr. J.M. Smit Paranimfen M.J. Schuijs MSc C.M. de Bruijn DVM, Dipl. ECEIM Beoordelingscommissie Prof. dr. N.A. Bos Prof. dr. M.S. Diamond Prof. dr. E.J.H.J. Wiertz

5 Say not, I have found the truth, but rather, I have found a truth. Kahlil Gibran ( ) The Prophet, Chapter 17: On Self-knowledge

6 Table of contents Chapter 1: Brief introduction and scope of thesis 9 Chapter 2: A review into the molecular mechanisms involved in antibody-dependent enhancement of dengue virus infection in humans. The trafficking of dengue virus within its host cells may be different when the virus enters via antibody-fc receptors, compared to entry in absence of antibodies. Antibody-dependent enhancement (ADE) can be categorized into intrinsic ADE and extrinsic ADE. Intrinsic ADE entails immune suppression, whereas extrinsic ADE is the enhancement of the infected cell mass. 21 Chapter 3: Dengue tropism for macrophages and dendritic cells; the host cell effect. The increased tropism for macrophages during secondary infection may contribute to higher and prolonged viraemia. Dendritic cells are refractory to their own viruses, while not to macrophage-derived virions. Hence, dengue virus may cycle between those two cell types due to the differential susceptibility. 45 Chapter 4: Antibody-dependent enhancement of dengue virus infection in primary human macrophages; balancing higher fusion against antiviral responses. ADE is a unique phenomenon, tightly controlled by fusion and antiviral response. Antibody-dependent enhancement of dengue virus does not involve immune-suppression. Early interferon responses determine the efficiency of dengue virus infection. Increased virus production per cell is not solely dependent on the mode of entry. 63

7 Chapter 5: The effect of tumour necrosis factor alpha, interleukin 6, and interferon alpha on dengue virus infection and production in primary human macrophages. Neither tumour necrosis factor alpha nor interleukin 6 enhance dengue infectivity on primary macrophages Early application of interferon alpha significantly suppresses dengue infectivity The efficacy of interferon alpha strongly depends on the viral dose and time point of application, thus limiting its therapeutic value 95 Chapter 6: The complexity of a dengue vaccine: A review of the human antibody response. Epitope mapping did not find a single epitope responsible for universal neutralization of disease in vitro and in vivo Although the TDV-CYD vaccine show limited efficacy against virologically confirmed disease, it significantly reduced hospitalization and severe forms of dengue The antibody repertoire differs between primary and secondary infections T cell responses might be more important than previously appraised 109 Chapter 7: Summarizing discussion 135 Chapter 8: Dutch summary / Nederlandse samenvatting 159 Dankwoord 166