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

B/Sleep-wake disturbances following tick-borne encephalitis (TBE)

(IRC project: Decoding Sleep: From Neurons to Health & Mind,  https://www.sleep.unibe.ch/)

Tick-borne encephalitis (TBE) affects the central nervous system. Over the last years, a steady increase in the incidence of TBE has been observed in Switzerland. Sleep-wake disorders are frequently reported by patients after tick-borne encephalitis (TBE). Altered sleep-wake functions, mainly hypersomnia, are frequent manifestations of acute viral meningoencephalitis. After the acute phase patients often still complain about sleep-wake disturbances and fatigue. Disabling tiredness or fatigue has been reported in up to 22% of TBE patients at 6-month follow up after the acute disease and in up to 32% after 10 years. This may be caused by inflammatory processes and/or damage of specific brain areas (e.g. thalamus, hypothalamus). We hypothesize that in experimental murine viral encephalitis, altered sleep-wake changes occur after infection and accordingly histopathological changes/damage can be found in different structures, including thalamus, hypothalamus and mesencephalon. Further we hypothesize the onset and/or severity of sleep-wake changes during or consecutive to TBE results either from apoptosis, necrosis or physiological dysfunction of the infected neuronal cells or from other molecular changes indirectly induced by the resulting inflammatory response.  In this project, we will a) assess the presence of persistent changes in sleep pattern in an established model of experimental viral encephalitis induced by Langat Virus and b) identify histo-patho-morphological features and molecular changes elucidating pathophysiologic mechanisms leading to sleep and behavioral disorders in the acute and post TBE phases of the disease

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

(Funded by the Multidisciplinary Center for Infectious Diseases, https://www.mcid.unibe.ch/)

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)

D/ Assessing correlation of high-resolution imaging with biomarkers, histomorphometry and neurofunction in rodent models of brain damage due to inflammation and infection

(Sitem Insel support found, in collaboration with the Translation Imaging Center at Sitem)

Magnetic resonance imaging (MRI) is well-suited for replacing conventional histopathological methods in longitudinal in vivo studies in models of brain infections. In the framework of the TIC, we use the clinical 7T-scanner with a dedicated custom-made MRI coil that was developed in partnership with the High Field MR Center, Center for Medical Physics and Biomedical Engineering, Medical University of Vienna, Austria. Combined with the evaluation of novel biomarkers of neuronal damage, we will test new therapeutic concepts that attenuate brain damage and support brain repair in order to preserve neuro-integrative function e.g. learning and hearing capacity in long term survivors of bacterial meningitis and other infectious and inflammatory diseases of the brain.

(collaboration with Prof. Dr. med. Roland Wiest, Professor of Advanced Neuroimaging, University of Bern, Vice Chair, Institute of Diagnostic and Interventional Neuroradiology)

E/ 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.