Modifications of the Staphylococcus aureus cell envelope and their roles in host microbe interactions [Elektronische Ressource] / von Dirk Kraus

Dkkraus

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Informations

• Publié par: eberhard_karls_universitat_tubingen
• Publié le: 01 janvier 2007
• Nombre de lectures: 5
• Langue: English
• Poids de l'ouvrage: 3 Mo

Extrait

Modifications of the Staphylococcus aureus cell envelope
and their roles in host-microbe interactions



der Fakultät für Biologie

der EBERHARD KARLS UNIVERSITÄT TÜBINGEN

zur Erlangung des Grades eines Doktors

der Naturwissenschaften

von

Dirk Kraus

aus Albstadt-Ebingen

vorgelegte

D i s s e r t a t i o n

2007





















Tag der mündlichen Prüfung: 7. Dezember 2007

Dekan: Prof. Dr. H. Mallot

1. Berichterstatter: Prof. Dr. A. Peschel

2. Berichterstatter: PD Dr. C. Wolz


















Meiner Familie
Contents


1
Summary

2
Introduction

Muropeptide Modification-Amidation of Peptidoglycan D-Glutamate Does 17
Not Affect the Proinflammatory activity of Staphylococcus aureus

Molecular Basis of Resistance to Muramidase and Cationic Antimicrobial 28
Peptide Activity of Lysozyme in Staphylococci

The GraRS regulatory system controls Staphylococcus aureus 69
susceptibility to antimicrobial host defences

The mammalian ionic environment dictates microbial susceptibility to 82
antimicrobial defense peptides

Large-conductance calcium-activated potassium channel activity is absent 104
in human and mouse neutrophils and is not required for innate immunity

129Discussion

139References (Introduction and Discussion)

155Contribution to the publications

Review: Molecular mechanisms of bacterial resistance to antimicrobial 156
peptides

157
Curriculum vitae

Summary
__________________________________________________________________________________________
Summary

Staphylococcus aureus is a frequent constituent of human nasal flora and a major
cause of severe infections. In order to successfully establish infections, S. aureus
has evolved several mechanisms to resist and evade the human innate immune
system (36).
One mechanism is the neutralization of the cell surface net charge by dlt-mediated
incorporation of positively charged alanine residues into teichoic acids (99). In this
work we could show that dlt-mediated alanylation is regulated by the novel two-
component regulatory system GraRS and that this regulation is crucial for S. aureus
CAMP resistance and virulence. However, the detailed mechanisms concerning
activating stimuli and involved regulatory proteins remained unknown.
CAMPs have many functions in the innate immune response. The fact that they show
rather weak killing activity when tested under culture conditions with physiological
NaCl concentrations or serum (13) led to a debate as to the true relevance of these
peptides in direct inactivation of microorganisms. Here we could show, that
carbonate ions are essential to render bacteria susceptible to CAMPs. The presence
of carbonate leads to dramatic alterations of bacterial transcriptional profiles and cell
wall structure. However, the detailed mechanisms that lead to increased
susceptibility to CAMPs in the presence of carbonate remained unknown.
Neutrophils are the first-line cell defense of the innate immune system. They
inactivate pathogens by production of CAMPs and by the oxidative burst. Former
2+ +publications postulated a role of BK-channels (big conductance Ca -activated K -
channels) in production of toxic, oxygen-containing molecules, and consequently, in
innate antimicrobial host defense (1). In this work we could show, that BK- channels
are absent in neutrophils and are not essential in combating invading pathogens.
Besides the resistance against innate antimicrobial defenses, evasion of recognition
by receptors of the innate immune system is essential to establish an infection.
Recent studies have shown, that modifications of muropeptides strongly impair
recognition of peptidoglycan structures by receptors such as NOD1 (19,44). S.
aureus modifies its muropeptides by D-glutamate amidation. However, we could not
detect an impact of muropeptide amidation on the immune stimulating capacity of S.
aureus in this work. The role of this modification on CAMP resistance e.g. could be
an interesting question for future studies.

1