Pneumococcal Meningitis
Streptococcus pneumoniae (pneumococcal) meningitis is the most common form of bacterial meningitis [1]. At risk are mostly children and immunosupressed patients. The epidemiological situation is especially serious in Third World countries, where more pathogenic strains exist. The patient survival rate is 75%; however, half of the patients suffer from long-term disabilities [2]. This disease is associated with significant but not massive neuronal death, predominantly in the hippocampus [3]. In bacterial meningitis, pathogenic bacteria multiply in the CSF and are abundant adjacent to the white matter (along the ventricles) and the neocortex. Currently, all therapeutic approaches are limited to antibiotic and symptomatic therapy, which have limited effectiveness.
We focus on major factors of bacterial damage, namely - the capsule, the cytolysin pneumolysin and their crosstalk with the host cells of the brain - neurons, synapses, and microglia.
Cholesterol-dependent cytolysins
|
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., 2006; 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.
|
|
|
Our research
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; C. 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 (Carolin 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 (Carolin Wippel et al., 2013).
|