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

Abstract

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 twocomponent 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 publications postulated a role of BK-channels (big conductance Ca2+-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.

Modifikationen der Staphylococcus aureus-Zellhülle und ihre Rolle in der Wirts-/Pathogen Interaktion