Type VII secretion - VU-DARE Home - Vrije Universiteit Amsterdam

151 Pages·2008·3.51 MB·English

PROTEIN SECRETION AND VIRULENCE IN
PATHOGENIC MYCOBACTERIA

Abdallah M. Abdallah
Title: Protein Secretion and Virulence in Pathogenic Mycobacteria

Abdallah Musa Abdallah
Thesis Vrije Universiteit Amsterdam, with summary in Dutch
Cover:
Front: Mycobacterium marinum supplemented with DsRed
Back: The Arab-Islamic Origins of Modern Science:
Copy of Avicenna’s five-volume Canon of Medicine, which is the
most famous of all medical books in history. It was the final
authority in medical matters in Europe for nearly six centuries.
Avicenna {Ibn Sina} was a universal genius, who was called "the
prince of physicians" in the West and considered the father of
modern medicine, and regarded as one of the greatest thinkers
and medical scholars in history.
An Islamic Astrolabe; the Astrolabe {Astrology and Astronomy}
was highly developed in the Islamic world and was introduced to
Europe from Islamic Spain {Andalusia} in the early 12th century.
Photograph: W. Bitter, Vrije Universiteit Medical Centre, Amsterdam
W. Müller, Utrecht Uiversity, Utrecht, The Netherlands
Cover design: ACSMedia
Printed by: PrintPartner Ipskamp, Enschede, The Netherlands

ISBN: 978-90-9022779-5

Publication of this thesis was financially supported by KNCV Tuberculosis
Foundation, Wyeth Pharmaceuticals B.V., Pfizer B.V., Bayer HealthCare, and
Promega Benelux B.V.

Copyright © 2008 by A.M. Abdallah

All rights reserved. No part of the material protected by this copyright notice may
be reproduced or utilized in any form or by any means, electronic or mechanical,
including photocopying, recording or by any information storage and retrival
system, without written permission from the author, or from publishers of the
publications.
VRIJE UNIVERSITEIT

PROTEIN SECRETION AND VIRULENCE IN
PATHOGENIC MYCOBACTERIA

ACADEMISCH PROEFSCHRIFT

ter verkrijging van de graad Doctor aan
de Vrije Universiteit Amsterdam,
op gezag van de rector magnificus
prof.dr. L.M. Bouter,
in het openbaar te verdedigen
ten overstaan van de promotiecommissie
van de faculteit der Geneeskunde
op dinsdag 11 maart 2008 om 10.45 uur
in de aula van de universiteit,
De Boelelaan 1105

door
Abdallah Musa Abdallah
geboren te Elobeid, Sudan
promotor prof.dr. C.M.J.E. Vandenbroucke-Grauls
copromotor dr. W. Bitter
“Science knows no country, because knowledge belongs to humanity, and it is the
torch, which illuminates the world”

Louis Pasteur (1822-1895)

To my family and friends
Doctoral Committee
Other members:
Prof. dr. Stewart Cole
Global Health Institute, Lausanne, Switzerland
Prof. dr. T.H.M. Ottenhoff
Leiden University Medical Center, Leiden, the Netherlands
Prof. dr. P. Peters
Netherlands Cancer Institute, Amsterdam, the Netherlands
Prof. dr. Y. van Kooyk
VU University Medical Centre, Amsterdam, the Netherlands
Dr. J. Luirink
Vrije Universiteit, Amsterdam, the Netherlands

The studeis described in this thesis were performed at the Department of Medical
Microbiology and Infection Control of the VU University Medical Centre, van der
Boechorstraat 7, 1081 BT Amsterdam, the Netherlands.
CONTENTS

Chapter 1 Introduction 9

Chapter 2 Type VII--mycobacteria show the way 19
(Nat. Rev. Microbiol. 5:883-891, 2007)

Chapter 3 Mycobacterium marinum strains can be divided into two 47
distinct types based on genetic diversity and virulence
(Infect. Immun. 72:6306-6312,2004)

Chapter 4 A specific secretion system mediates PPE41 transport in 63
pathogenic mycobacteria (Mol. Microbiol. 62:667-679, 2006 )

Chapter 5 Mycobacterial PPE and PE_PGRS proteins are transported 87
via a type VII secretion system (Submitted for puplication)

Chapter 6 The ESX-5 secretion system of Mycobacterium Marinum 109
modulates the macrophage response
(Manuscript in preparation)

Chapter 7 General Discussion 129

Chapter 8 Summary and Samenvatting 139
Acknowledgements 145
Curriculum Vitae 148
List of publications 149

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Chapter 1: Introduction and outline of the thesis 10

Tuberculosis
Tuberculosis (TB) is a devastating disease that has already been present in the
human population since prehistoric times. Tuberculosis is primarily caused by the
high GC-gram positive bacterium Mycobacterium tuberculosis, but it can also be caused
by several closely related mycobacterial species belonging to the so-called M.
tuberculosis complex. The earliest detection of a member of the M. tuberculosis
complex is in the remains of a North American bison dated 17,000 years before
the present (BP)1. Detection of M. tuberculosis complex DNA in humans dates back
to the iron age, approximately 2,000-2,200 years BP2,3, but skeletal malformations
indicate that tuberculosis has been a human disease before this time. For instance,
tubercular decay has been found in the fragments of the spinal column of Egyptian
mummies from 3,000-2,400 BP4. Interestingly, ancient cases of TB were also
present in South America for almost 2,000 years5, which means long before the
arrival of Columbus or the Vikings. These results indicate that tuberculosis was
probably already introduced in the Americas during the first waves of human
migration. The first description of tuberculosis is by Hippocrates in ancient
Greece, who used the term “phthisis” for the disease. He describes phthisis as a
widespread disease and that patients had fever and were coughing up blood and
noted that it was almost always fatal.
Today, tuberculosis is still one of the most devastating infectious diseases.
Globally, about one-third of the world population is believed to be infected with
the tuberculosis bacillus and new carriers occur at a rate of one per second6. Only a
small minority of people infected with tuberculosis bacillus (5-10%) develops
active disease, whereas the vast majority of infected healthy individuals neither
develop disease nor become infectious. However, they are usually unable to kill all
bacilli, leading to a latent tuberculosis infection7. 5-10% of people with latent
tuberculosis develop full-blown disease years or decades after the initial infection8.
In total more than 8 million people become sick with tuberculosis every year, and
nearly two million die of the disease. This is the highest rate claimed by a single
infectious bacterial agent6. Recently, Stop Tuberculosis Partnership initiated an
ambitious and intensive eradication programme, the Global Plan to Stop
Tuberculosis with the long-term target of eliminating tuberculosis as a global
public health problem9. With a combination of Bacille Calmette–Guerin (BCG)
vaccination and extensive treatment of tuberculosis cases with anti-mycobacterial
drugs, one hopes to be able to deal with the tuberculosis problem once and for all.
However, since a few decades developing countries are dealing with a strong
resurgence of tuberculosis, such that more people are now suffering from
tuberculosis than ever before. Different factors have contributed to this resurgence
and precarious global situation, including (i) the variable efficacy of the BCG
vaccine, (ii) the emergence of multi-drug resistant M. tuberculosis strains, (iii) the co-
infection with another deadly pathogen, HIV; and (iv) factors that affect the
public-health system, such as continuing political instability and war, poverty,
natural disasters and more frequent transmission due to an increased human