Cytoskeleton and Rho GTPases as targets of Streptococcus pneumoniae pneumolysin in meningitis and CNS dysfunction
Final Report Abstract
The project by the DFG Emmy Noether Programme allowed us to design, organize and implement a research plan that revealed important aspects of the behavior of the cholesterol-dependent cytolysin pneumolysin in disease conditions. The combination between artificial membrane models, cell cultures, slice cultures, animal and human brain sample experiments allowed to establish a translational approach that generated substantial amount of results. These are: 1. In sub-lytic concentrations, pneumolysin can alter the actin cytoskeleton by direct transmembrane interaction with actin through the membrane. In primary astrocytes, the activation of small GTPases occurs secondary to the actin changes. 2. Pore forming capacity remains critically important for the cytoskeleton alterations by pneumolysin even when no cell lysis is observed. 3. Moderate changes in the extracellular calcium concentrations can have profound effects on the lytic capacity of the toxin. 4. Pneumolysin plays critical role in pneumococcal meningitis, leading to synaptic loss, dendritic damage, tissue remodeling and swelling partially in a glutamatedependent manner. The toxin exerts these effects not directly on neurons, but indirectly via astrocytes. 5. For the first time, we describe the occurrence of synaptic loss in the neocortex of patients with pneumococcal meningitis. This gives new insights into the cognitive disabilities of meningitis patients and changes our understanding of meningitis as a synaptic loss disease.
Publications
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Rapid microtubule bundling and stabilization by the Streptococcus pneumoniae neurotoxin pneumolysin in a cholesterol-dependent, non-lytic and Src-kinase dependent manner inhibits intracellular trafficking. Molecular Microbiology 2008, 71, 461-477
Iliev A.I., Djannatian J.R., Opazo F., Gerber J., Nau R., Mitchell T.J., Wouters F.S.
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Quantitative fluorescence microscopy techniques. Methods Mol Biol. 2009;586:117-142
Esposito A., Schlachter S., Schierle G.S., Elder A.D., Diaspro A., Wouters F.S., Kaminski C.F., Iliev A.I.
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Changes in Astrocyte Shape Induced by Sublytic Concentrations of the Cholesterol-Dependent Cytolysin Pneumolysin Still Require Pore-Forming Capacity. Toxins. 2011; 3(1):43- 62
Förtsch C., Hupp S., Ma J., Mitchell T.J., Maier E., Benz R., Iliev A.I.
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Extracellular calcium reduction strongly increases the lytic capacity of pneumolysin from streptococcus pneumoniae in brain tissue. J Infect Dis. 2011, 204(6):930-6
Wippel C, Förtsch C, Hupp S, Maier E, Benz R, Ma J, Mitchell TJ, Iliev AI
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Astrocytic tissue remodeling by the meningitis neurotoxin pneumolysin facilitates pathogen tissue penetration and produces interstitial brain edema. Glia 2012, 60(1):137-46
Hupp S, Heimeroth V, Wippel C, Förtsch C, Ma J, Mitchell TJ, Iliev AI
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Bacterial cytolysin during meningitis disrupts the regulation of glutamate in the brain, leading to synaptic damage. PLoS Pathog. 2013;9(6):e1003380
Wippel C, Maurer J, Förtsch C, Hupp S, Bohl A, Ma J, Mitchell TJ, Bunkowski S, Brück W, Nau R, Iliev AI
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Direct transmembrane interaction between actin and the pore-competent cholesterol-dependent cytolysin pneumolysin extends the cellular role of pore formation. J Mol Biol 2013, 425(3):636- 46
Hupp S, Förtsch C, Wippel C, Ma J, Mitchell TJ, Iliev AI
