Research

Molecular Neuroinfectiology

Research

Introduction

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).

Current projects

  • 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.