Department for BioMedical Research (DBMR)

Regenerative Neuroscience - RNS

Leib Lab 2

Ongoing Projects

A/ Shedding light on the pathophysiology of pneumococcal and listeric meningitis by complementary disease models and non- invasive methods to evaluate novel therapeutics

SNF-funded

The overarching aim of the present proposal is to deepen our yet incomplete understanding of the pathophysiology of brain infections. Here we focus on bacterial meningitis caused by the most destructive forms i.e. infections caused by Streptococcus pneumoniae and Listeria monocytogenes. We propose to introduce new approaches involving alternative disease models e.g. zebrafish embryos, evaluate novel biomarkers e.g. axonal protein neurofilament light chain (NFL) and introduce newly developed imaging techniques e.g. 7 Tesla magnetic resonance imaging to deepen our understanding of the disease processes and identify novel targets for therapy

Figure 1: Zebrafish larvae infected with microinjection of GFP-producing S.pneumoniae in the hindbrain region, 24 hours after infection. The development of central nervous system infection can be identified along the spinal cord (B) and hindbrain region (C) by fluorescence microscop

B/ Confronting the rising epidemic of the zoonotic tick-borne encephalitis virus

Funded by the Multidisciplinary Center for Infectious Diseases
Cerebellar brain section of experimental TBE in rats at 4 days after infection with Langat virus. Viral antigens (red) are present in specific regions of the cerebellum Flaviviruses are transmitted by arthropods to humans and are responsible for increasing numbers of outbreaks due to climate change and globalization. Some are causing severe neurological disorders, with long-lasting consequences or even death and treatment options are lacking. To better understand the mechanisms of disease, we will exemplary study tick-borne encephalitis (TBE) virus, that represents a significant concern in Europe. We will use complementary approaches including human cerebral organoids and rodent brain organotypic cultures complemented with an experimental in vivo model of TBE. The efficient screening and validation of potential antiviral molecules represents an additional objective of the project.
Collaboration with PD Dr Marco Alves, Institut für Virologie und Immunologie, Vetsuisse.

Cerebellar brain section of experimental TBE in rats at 4 days after infection with Langat virus. Viral antigens (red) are present in specific regions of the cerebellum

D/ Use of bacteriophages / endolysin as alternative strategies for the treatment of antibiotic-resistant infections

in collaboration with the Department of Intensive Care Medicine, Insel Hospital, Bern
Bacteriophages are ubiquitous bacterial viruses. After their discovery in the beginning of the 20th century, phages have been used as therapeutic agents for the treatment of human bacterial infections. However, due to the discovery of antibiotics phage-based therapies in the western world despite proven efficacy. With the rapid spread of multi-drug resistant bacteria, phage therapy regained popularity and is considered as a very promising alternative/complementary strategy for the treatment of complex infections. Similar to phage therapy, endolysin therapy is a promising non-antibiotic based, highly efficient antibacterial treatment. Endolysins (or lysins) are phage-encoded enzymes which have peptidoglycan hydrolase activity and are therefore able to degrade the bacterial cell wall, allowing the virus to escape the host cell after replication. Initial in vitro and in vivo data are very promising, displaying an impressive efficacy in lysing bacterial cells including multi-drug resistant bacteria. In addition, endolysins are (i) highly specific and are unlikely to disturb the normal microflora (ii) not associated with any emergence of resistance, or (iii) any noxious effects after topical intravenous or intraperitoneal application.
The present research project is focused on evaluating bacteriophages and endolysins for treatment of different infectious conditions elicited by antibiotic-resistant strains.
(i) Ventilator-associated pneumonia due to MRSA,
(ii) bacterial meningitis due to ceftriaxone-resistant pneumococci and
(iii) catheter associated blood-stream infections due to MRSA and MDR S. epidermidis