University of Groningen Tackling challenges to tuberculosis elimination Gröschel, Matthias Ingo Paul

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University of Groningen

Tackling challenges to tuberculosis elimination

Gröschel, Matthias Ingo Paul

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Publication date: 2019

Link to publication in University of Groningen/UMCG research database

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Gröschel, M. I. P. (2019). Tackling challenges to tuberculosis elimination: Vaccines, drug-resistance, comorbidities. University of Groningen.

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Tackling Challenges of

Tuberculosis Elimination

Vaccines, Drug-resistance, Comorbidities

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The work described herein was conducted at the Department of Pulmon-ary Diseases & Tuberculosis at the University Medical Center Groningen, University of Groningen (The Netherlands), the Unit for Integrated Myco-bacterial Pathogenomics at Institut Pasteur, Paris (France) and the Molecu-lar and Experimental Mycobacteriology laboratory at the Research Center Borstel, Leibniz Lung Center, Borstel (Germany).

Printing of this thesis was financially supported by the KNCV Tubercu-losis Foundation, the Stichting Beatrixoord Noord Nederland, the Gradu-ate School of Medical Sciences of the University of Groningen, the Univer-sity of Groningen library, and the Department of Pulmonary Diseases & Tuberculosis at the University Medical Center Groningen. This support is greatly appreciated.

Cover design Angela Kahle, Seligenstadt, Germany Cover illustration iStockphoto BerSonnE

Print GVO drukkers & vormgevers B.V. Ede, The Netherlands

ISBN 978-94-034-1433-1

c

 Matthias Gr¨oschel

Tackling Challenges of

Tuberculosis Elimination

Vaccines, Drug-resistance, Comorbidities

PhD thesis

to obtain the degree of PhD at the

University of Groningen

on the authority of the

Rector Magnificus Prof. E. Sterken

and in accordance with

the decision by the College of Deans.

This thesis will be defended in public on

Monday, April 1

th

_{, 2019 at 16:15 hours}

by

Matthias Ingo Paul Gr¨oschel

born on September 20

th

_{, 1988}

(4)

The work described herein was conducted at the Department of Pulmon-ary Diseases & Tuberculosis at the University Medical Center Groningen, University of Groningen (The Netherlands), the Unit for Integrated Myco-bacterial Pathogenomics at Institut Pasteur, Paris (France) and the Molecu-lar and Experimental Mycobacteriology laboratory at the Research Center Borstel, Leibniz Lung Center, Borstel (Germany).

Printing of this thesis was financially supported by the KNCV Tubercu-losis Foundation, the Stichting Beatrixoord Noord Nederland, the Gradu-ate School of Medical Sciences of the University of Groningen, the Univer-sity of Groningen library, and the Department of Pulmonary Diseases & Tuberculosis at the University Medical Center Groningen. This support is greatly appreciated.

Cover design Angela Kahle, Seligenstadt, Germany

Print GVO drukkers & vormgevers B.V., Ede, The Netherlands ISBN 978-94-034-1433-1

c

 Matthias Gr¨oschel

Tackling Challenges of

Tuberculosis Elimination

Vaccines, Drug-resistance, Comorbidities

PhD thesis

to obtain the degree of PhD at the

University of Groningen

on the authority of the

Rector Magnificus Prof. E. Sterken

and in accordance with

the decision by the College of Deans.

This thesis will be defended in public on

Monday, April 1

th

_{, 2019 at 16:15 hours}

by

Matthias Ingo Paul Gr¨oschel

born on September 20

th

_{, 1988}

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Supervisors

Prof. T. S. van der Werf

Prof. R. Brosch

Prof. S. Niemann

Assessment committee

Prof. J. M. van Dijl

Prof. M. Grobusch

Prof. B. de Jong

Paranymphs

Eva Boritsch

Xaver Kahle

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Supervisors

Prof. T. S. van der Werf

Prof. R. Brosch

Prof. S. Niemann

Assessment committee

Prof. J. M. van Dijl

Prof. M. Grobusch

Prof. B. de Jong

Paranymphs

Eva Boritsch

Xaver Kahle

(7)

Meinem Großvater

Introduction

I have come to think that tuberculosis (...) is no special disease, or not a disease that deserves a special name, but only the germ of death itself.

Franz Kafka

An ancient disease

Humans have always cohabited the planet replete with fellow organisms of diverse species, of various sizes and scales. The genus Mycobacterium and its paramount representative Mycobacterium tuberculosis are an example of concomitant evolution of a pathogen with its exclusive host across the timeline of human prehistory1_{. Tuberculosis (TB) in humans is a chronic}

infection mostly affecting the lungs and is caused by pathogens of the M.

tuberculosis complex (MTBC). Infection occurs via aerosol transmission and

can lead to either latent or active TB disease. While one quarter of the global population are estimated to be latently infected, defined as a meas-urable immune response to M. tuberculosis antigens in whole blood, 5-10% will develop active TB at some time in their lives2_{. The main symptoms}

include cough, fever, night-sweats, and weight loss and effective treatment for drug-susceptible strains with a combination of four antimicrobials is available.

TB is an ancient disease. Despite sophisticated molecular techniques, the discussion about the geographic origin and historic provenance of M.

tuberculosis has not entirely settled. The oldest evidence of human

infec-tion was detected in the 9.000 year-old remains of a woman and infant that had lived in an early-Neolithic settlement in the Eastern Mediterranean3_.

University of Groningen Tackling challenges to tuberculosis elimination Gröschel, Matthias Ingo Paul

University of Groningen

Tackling challenges to tuberculosis elimination

Gröschel, Matthias Ingo Paul

Tackling Challenges of

Tuberculosis Elimination

Tackling Challenges of

Tuberculosis Elimination

Vaccines, Drug-resistance, Comorbidities

PhD thesis

to obtain the degree of PhD at the

University of Groningen

on the authority of the

Rector Magnificus Prof. E. Sterken

and in accordance with

the decision by the College of Deans.

This thesis will be defended in public on

Monday, April 1

, 2019 at 16:15 hours

by

Matthias Ingo Paul Gr¨oschel

born on September 20

, 1988

Tackling Challenges of

Tuberculosis Elimination

Vaccines, Drug-resistance, Comorbidities

PhD thesis

to obtain the degree of PhD at the

University of Groningen

on the authority of the

Rector Magnificus Prof. E. Sterken

and in accordance with

the decision by the College of Deans.

This thesis will be defended in public on

Monday, April 1

, 2019 at 16:15 hours

by

Matthias Ingo Paul Gr¨oschel

born on September 20

, 1988

Supervisors

Prof. T. S. van der Werf

Prof. R. Brosch

Prof. S. Niemann

Assessment committee

Prof. J. M. van Dijl

Prof. M. Grobusch

Prof. B. de Jong

Paranymphs

Eva Boritsch

Xaver Kahle

Supervisors

Prof. T. S. van der Werf

Prof. R. Brosch

Prof. S. Niemann

Assessment committee

Prof. J. M. van Dijl

Prof. M. Grobusch

Prof. B. de Jong

Paranymphs

Eva Boritsch

Xaver Kahle

Contents

I Vaccines

21

II Drug-resistance

167

III Comorbidities

197

IV Appendix

269

Contents

I Vaccines

21

II Drug-resistance

167

III Comorbidities

197

IV Appendix

269

_{, 2019 at 16:15 hours}

_{, 1988}

_{, 2019 at 16:15 hours}

_{, 1988}