Funktionelle Charakterisierung neuer Virulenzfaktoren von Staphylococcus aureus [Elektronische Ressource] = Funktionelle Charakterisierung neuer Virulenzfaktoren von Staphylococcus aureus / vorgelegt von Dorothee Grumann

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Sujets

• Biologie

Informations

• Publié par: ernst-moritz-arndt-universitat_greifswald
• Publié le: 01 janvier 2010
• Nombre de lectures: 28
• Poids de l'ouvrage: 8 Mo

Extrait

Funktionelle Charakterisierung neuer Virulenzfakteonr
von Staphylococcus aureus

(Functional chracterization of new virulence sf actor
of Staphylococcus aureus)



I n a u g u r a l d i s s e r t a t i o n
zur
Erlangung des akademischen Grades
doctor rerum naturalium (Dr. rer.nat.)
an der Mathematisch-Naturwissenschaftlichen Fakutl tä
der
Ernst-Moritz-Arndt-Universität Greifswald

vorgelegt von
Dorothee Grumann
geboren am 03.01.1980
in Fürth

Greifswald, 11.03.2010
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dekan:    Prof. Dr. Klaus Fesser 
 
1. Gutachter:    Prof. Dr. Barbara M. Bröker 
2. Gutachter:    Prof. Dr. Alex F. van Belkum 
 
Tag der Promotion:  09. Juli 2010 
 
CONTENTS

PART I NTIRODUCTION
Chapter 1 Staphylococcus aureus in disease and in health………………………….........1. ..........
1.1 S. aureus – human pathogen and harmless commensal………………………2
1.2 S. aureus comparative genomics……………………………………………………….4
1.3 What determines staphylococcal virulence?............................................6
1.4 Staphylococcal superantigens…………………………………………………………..7
1.5 Outline of the thesis……………………………………………………………………… .14

PART II ESURLTS
Chapter 2 Clonal distribution of superantigen ginen ecslinicSatla phylococcus
aureus isolates.
S. Holtfreter, D. Grumann, M. Schmudde,u yHe.n , TP.. TE.i chNlegr, B.
Strommenger, K. Kopron, J. Kolata, S. Gbiead,r ysI-K.a leSmteinmetz, W.
Witte, and B. M. Bröker. 2007. J Clin2 66M9i-c2r6o8bi0o…l …4…5…:…....24

Chapter 3 Diversity of prophages in domStianpahnytl ococcus aureus clonal lineages.
C. Goerke, R. Pantucek, S. Holtfreter, MB.. ZSinchku,l teD,. Grumann, B. M.
Bröker, J. Doskar, and C. Wolz. 2009.9 1:J3 4B6a2c-3te4r6io8l …1…………39

Chapter 4 Recurrent furunculosis - associatiohn s Pwaniton-Valentine leukocidin
and the genetic backgroundSt aopfh ylococcus aureus .
H. Masiuk, K. Kopron, D. Grumann, C. aGtoa,er kJe., JJu.r saK-oKlulesza, S.
Giedrys-Kalemba, B. M. Bröker, and S. H0o1lt0fr.e teirn. p2ress……………47

Chapter 5 Anti-staphylococcal humoral immune rsees poin persistent nasal carriers
and noncarriers Sotfa phylococcus aureus.
iii
N. J. Verkaik, C. P. de Vogel, H. uAm. anBno,e leTn.s, HDo.o geGnrboezem,
C. Vink, H. Hooijkaas, T. J. Foster, H,. AA.. vVaenr bBrueglkhum, and W. J.
van Wamel. 2009. J I n1f9e9c:t6 2D5i-s632…………………………………………..69

Chapter 6 Neutralizing antibody responsSet apthoy lococcus aureus superantigens in
bacteremic patients.
D. Grumann, E. Ruotsalainen, J. Kolata, AP. JKäuruvsinelean,, V. P.
Kontinen, B. M. Bröker, and S. Holtfretbemr.it te2d0…1…0….… …su............78

Chapter 7 Immune cell activation by enterotoex incl usgtenr eg(c)-encoded and
non-egc superantigens froSmta phylococcus aureus.
D. Grumann, S. S. Scharf, S. Holtfrete r,L . C.S teKilo,h leSr., Engelmann, M.
Hecker, U. Völker, and B. M. Bröker. 20l 1081.: 50J 54I-m50m6u1n…o…96

PART III UMSMARY
Chapter 8 Summary and discussion…………………………………………………………...116
8.1 What determines staphylococcal virulence?u laMr-eopleidcemiology
of colonizing and invasSi.v ea ureus isolates……………………………….…117
8.2 Anti-staphylococcal antibody response inz atciolno niand
bacteremia………………………………………………………………………………..…122
8.3 Comparison egocf and noeng-c superantigens – What is the reason
for the lack of eagnc ti-antibodies?....................................................................125

PART IV PAPENDIX
Summary…………………………………………………………………………………………..135
Zusammenfassung……………………………………………………………………………..138
Abbreviations……………………………………………………………………………………142
Publications………………………………………………………………………………………145
iv
Conferences……………………………………………………………………………………....146
Acknowledgments/ Danksagung………………………………………………….…….418
Eidesstattliche Erklärung…………………………………………………………………..150
Curriculum vitae……………………………………………………………………………..…15 1


v

Chapter 1

Staphylococcus aureus in disease and in health


1 STAPHYLOCOCCUS AUREUS IN DISEASE AND IN HEAL TH

Staphylococcus aureus in disease and in health
Staphylococcus (S.) aureu is an opportunistic pathogen and a leading cause o f bacterial
infections worldwide. The spread of antibiotic resi stant strains in hospitals as well as in
the healthy population is of growing concern. Moreo ver, up until now, no anti- S. aureus
vaccine has been approved for medical practice (1).

1.1S . AUREUS – HUMAN PATHOGEN AND HARMLESS COMMENS AL
Clinical impact of S. aureus
S. aureus is a major human pathogen capable of causing a wid e spectrum of infections,
from relatively mild skin infections such as follic ulitis and furunculosis to life-
threatening diseases, including sepsis, pneumonia,os teomyelitis, and infective
endocarditis (2). Infections caused by this pathogne have increased over the past 25
years (2, 3S).. a ureus (methicillin-sensitive as well as methicillin-resistant S. aureus;
MSSA and MRSA, respectively) ranks as the most comm on cause of nosocomial
bloodstream infections and leads to increased morbi dity, mortality, length of hospital
stay, and costs (4).
The treatment of such infections is complicated by the ability of this species to become
resistant to antibiotics (5). MRSA strains are wide spread in nosocomial environments
(hospital-associated MRSA; HA-MRSA), and account for > 60% ofS . aureus isolates in US
intensive care units (6). Of growing concern is the emergence and spread of highly
pathogenic MRSA strains in the community outside th e hospital setting (community-
associated MRSA; CA-MRSA), especially the clone USA300 (7, 8). These strains cause
serious infections in otherwise healthy individuals (7, 9). Vancomycin is the drug of
choice for therapy of infections due to MRSA, but i ncrease in vancomycin use has led to
the emergence of vancomycin intermediate-resistent (VISA) or resistant strains (VRSA)
(10). As a consequence of increasing antibiotic resistance non antimicrobial approaches
to control S. aureus are needed. However, due to the complex interactio n between
S. aureus and the immune system of its host, vaccine develop ment is still a challenging
task.

2 STAPHYLOCOCCUS AUREUS IN DISEASE AND IN HEAL TH

S. aureus nasal carriage patterns
In apparent contrast with its infectious potential, S. aureus is also a frequent commensal
that colonizes the skin and mucosal surfaces of hum ans and several animal species (11).
The primary ecological niche of S. aureus are the anterior nares (11, 12). However,
multiple body sites can be colonized including the skin, perineum, pharynx, and less
frequently the gastrointestinal tract, vagina, and axillae (13). Longitudinal studies
distinguish three nasal carriage patterns in health y individuals: about 20% (range 12 -
30%) are persistent carriers, approximately 30% (rnage 16 - 70%) are intermittent
carriers, and about 50% (range 16 - 69%) are noncraierrs (13). While persistent
carriers are usually colonized by a single strain o f S. aureus, intermittent carriers
commonly carry different strains over time (14, 15). Cross-sectional studies yield a
prevalence of ~ 35% carriers in the healthy population, which is ac tually a mix of
persistent and intermittent carriers at the time of investigation (16, 17).
It is clinically relevant to distinguish between pe rsistent and intermittent carriers.
Persistent carriers have higher S. aureus loads, resulting in increased dispersal and a
higher risk of infection in comparison to intermitt ent carriers and noncarriers (13, 18-
21). Intermittent carriers and noncarriers show similar infection risks.
Recently van Belkum et al. suggested a reclassifica tion of nasal carriage types (21). An
artificial colonization study where volunteers were inoculated with a mixture of
S. aureus strains showed that intermittent carriers and nonc arriers quickly eliminated
the inoculated S. aureus strains, while persistent carriers preferentially r eselected their
original resident strain from the inoculum mixture (21, 22). Furthermore, the antibody
levels against 17 S. aureus antigens were equal in intermittent carriers and n oncarriers
but higher in persistent carriers. Along with the p reviously described low risk of
infection of intermittent carriers and noncarriers, the authors suggest to distinguish just
two types of nasal carriers: persistent carriers an d others.

What determines S. aureus nasal carriage?
Mechanisms leading to S. aureus nasal carriage appear to be multifactorial and are still
not fully understood. Bacterial factors (e.g. stapyhlococcal toxins and cell wall-
associated proteins) (2, 23), environmental factor (es.g. hospitalization and crowding)
(24, 25) as well as host susceptibility factors (ge.. immune suppre