Auswirkung von Glycopyrronium auf die Phagozytose von Streptococcus pneumoniae und Escherichia coli durch Makrophagen und Mikrogliazellen

Effect of glycopyrronium on the phagocytosis of Streptococcus pneumoniae and Escherichia coli by macrophages and microglial cells

by Elias Sándor Geisler
Doctoral thesis
Date of Examination:2021-11-10
Date of issue:2021-11-10
Advisor:Prof. Dr. Roland Nau
Referee:Prof. Dr. Dr. Helmut Eiffert
Referee:Prof. Dr. Margarete Schön
Persistent Address: http://dx.doi.org/10.53846/goediss-8927

 

 

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Abstract

English

Streptococcus pneumoniae and Escherichia coli are responsible for a wide variety of life-threatening infections such as pneumonia, sepsis, and meningitis. Multi-resistant pathogens are spreading more and more despite the implementation of vaccinations, since vaccination protection can only be guaranteed against a limited number of pneumococcal serotypes. Vaccination for Escherichia coli is only available to prevent urinary tract infections. Choline-binding proteins on the surface of at least all pneumococci act as virulence factors and thus offer a therapeutic target for combating pneumococcal infections. The inhibition of these choline-binding proteins by potent anticholinergics has already been used successfully to achieve increased phagocytosis of pneumococci through modified bacterial growth. In Escherichia coli, we suspected indirect inhibition via cholinergic transporters on the cell wall for the synthesis of glycine betaine and thus cell stability. In this work the effect of glycopyrronium on bacterial growth and bacterial phagocytosis by murine peritoneal macrophages, alveolar macrophages and microglial cells of Streptococcus pneumoniae and Escherichia coli was investigated. Glycopyrronium binds to cholinergic receptors and is mainly used to treat patients with chronic obstructive pulmonary disease. Improved lung function will reduce the number of exacerbations and possibly weaken an infection through an increased rate of phagocytosis. Streptococcus pneumoniae and Escherichia coli were incubated with glycopyrronium as they grew. In addition, they were co-incubated with the macrophages and microglial cells stimulated with glycopyrronium and toll-like receptor agonists to determine the phagocytic performance. Glycopyrronium did not influence the bacterial growth of Streptococcus pneumoniae and Escherichia coli in the concentrations investigated. It also did not affect the length of the cocci chains of Streptococcus pneumoniae. In addition, glycopyrronium had no effect on the ability of peritoneal and alveolar macrophages, as well as microglial cells, Streptococcus pneumoniae or Escherichia coli to phagocytize. Contrary to expectations, there was no indication in the experiments carried out here that glycopyrronium inhibited the choline-binding proteins of the pneumococci independently of the concentration. Likewise, no increased phagocytosis due to inhibition of cholinergic transporters on the cell wall of Escherichia coli was detectable for glycopyrronium in the experiments carried out here. Since glycopyrronium showed no impairment of bacterial phagocytosis of macrophages and microglial cells, it can be used safely as a therapeutic agent. On the one hand, glycopyrronium does not increase pulmonary infection susceptibility. On the other hand, the use of the drug during an existing infection does not lead to any harm. Even today, choline-binding proteins are still the focus of research as a target of antimicrobial therapy. By inhibiting these choline-binding proteins, the spread of all pneumococcal serotypes can be contained with a low probability of resistance developing.
Keywords: E. coli; S. pneumoniae; CBP; glycopyrronium; macrophages; COPD
 
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