Evolutionary, pathogenic bacteria developed various adaptive mechanisms to improve their ability to invade hosts. Bacterial toxins represent one of these adaptive approaches. While some toxins destroy cells (pore-forming toxins), other modulate cellular functions. Typical representatives of the pore-forming toxins are the cholesterol-dependent cytolysins (CDC) such as pneumolysin (from S. pneumoniae), perfringolysin (from C. perfringens), listeriolysin (from L. monocytogenes) and others. The presence of these toxins leads to much more complicated disease course. The pathogenic mechanisms extend beyond the pore-forming capacity, as actin remodeling, small GTPase activation, microtubule and cell shape changes take place (Iliev et al., 2007; Iliev et al., 2009; Hupp et al., 2012). These changes play critical role for the pathogenic effects in tissues, affected by the bacterial pathogen, altering their function.
The major focus of our group is to clarify the mechanisms of the CDC toxin effects on cells and tissues with special interest on brain tissue – specifically the astrocytes, synapses and blood-brain barrier. We are also interested in studying how the CDC toxins of meningitis-inducing bacteria (S. pneumoniae and L. monocytogenes) orchestrate the effects of the rest of the bacterial pathogenic factors (e.g. cell-wall components, bacterial DNA, etc.) during disease progression. In the last few years, we have clarified the role of pneumolysin as a major factor that modifies the shape and function of brain astrocytes in pneumococcal meningitis, producing complex brain tissue changes (Förtsch et al., 2011; Wippel et al., 2011; Hupp et al., 2012 ). An important component of these alterations is the release of glutamate from astrocytes, leading to an NMDA-dependent synaptic loss (Wippel et al., 2013). This finding underlines the importance of synaptic protection in meningitis, as it becomes apparent that synaptic loss plays more important role in such infectious diseases of the brain as previously believed (Wippel et al., 2013).
- Role of listeriolysin in synaptic damage and synaptic loss in meningitis models.
- Crosstalk among pneumolysin, cell wall components and bacterial DNA in synaptic damage and mechanisms of pharmacological modulation.
- Toxin-orientated strategies for neuroprotection in bacterial meningitis.
- Mechanism of glial cell modulation by toxins and pharmacological modulation.
Currently, the group is funded by the Swiss National Fund (SNF) and the University of Bern.
- Prof. Tim Mitchell, University of Birmingham
- Prof. Roland Nau, Neuropathology, University of Göttingen
- Prof. Wolfgang Brück, Neuropathology, University of Göttingen
- Prof. Annette Draeger, Anatomy, University of Bern
Förtsch, C., Hupp, S., Ma, J., Mitchell, T. J., Maier, E., Benz, R. and Iliev, A. I. (2011) 'Changes in Astrocyte Shape Induced by Sublytic Concentrations of the Cholesterol-Dependent Cytolysin Pneumolysin Still Require Pore-Forming Capacity', Toxins, 3(1), pp. 43-62. PubMed
Hupp, S., Heimeroth, V., Wippel, C., Fortsch, C., Ma, J., Mitchell, T. J. and Iliev, A. I. (2012) 'Astrocytic tissue remodeling by the meningitis neurotoxin pneumolysin facilitates pathogen tissue penetration and produces interstitial brain edema', Glia, 60(1), pp. 137-46. PubMed
Iliev, A. I., Djannatian, J. R., Opazo, F., Gerber, J., Nau, R., Mitchell, T. J. and Wouters, F. S. (2009) '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', Mol Microbiol, 71(2), pp. 461-77. PubMed
Iliev, A. I., Djannatian, J. R., Nau, R., Mitchell, T. J. and Wouters, F. S. (2007) 'Cholesterol-dependent actin remodeling via RhoA and Rac1 activation by the Streptococcus pneumoniae toxin pneumolysin', Proc Natl Acad Sci USA, 104(8), pp. 2897-902. PubMed
Wippel, C., Fortsch, C., Hupp, S., Maier, E., Benz, R., Ma, J., Mitchell, T. J. and Iliev, A. I. (2011) 'Extracellular calcium reduction strongly increases the lytic capacity of pneumolysin from streptococcus pneumoniae in brain tissue', The Journal of infectious diseases, 204(6), pp. 930-6. PubMed
Wippel, C., Maurer, J., Förtsch, C., Hupp, S., Bohl, A., Ma, J., Mitchell, T. J., Bunkowski, S., Brück, W., Nau, R. and Iliev, A. I. (2013) 'Bacterial Cytolysin during Meningitis Disrupts the Regulation of Glutamate in the Brain, Leading to Synaptic Damage', PLoS pathogens, 9(6), p. e1003380. PubMed