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

English title Shedding light on the pathophysiology of pneumococcal and listeric meningitis by complementary disease models and non- invasive methods to evaluate novel therapeutics
Applicant Leib Stephen L.
Number 189136
Funding scheme Project funding (Div. I-III)
Research institution Institut für Infektionskrankheiten Universität Bern
Institution of higher education University of Berne - BE
Main discipline Immunology, Immunopathology
Start/End 01.10.2019 - 30.09.2023
Approved amount 583'774.00
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All Disciplines (2)

Discipline
Immunology, Immunopathology
Pathophysiology

Keywords (10)

brain infection; Neurofilament; hearing loss; 7 Tesla magnetic resonance imaging ; neurofunctional sequelae; brain injury; Streptococcus pneumoniae; memory; bacterial meningitis; Listeria monocytogenes

Lay Summary (German)

Lead
Bakterielle Meningitis, insbesondere verursacht durch Infektion mit Pneumokokken und Listerien, ist eine schwere Infektion des zentralen Nervensystems. Trotz Fortschritte in der Prävention und Behandlung führt die Krankheit immer noch in bis zu 20% der Fälle zum Tod und hinterlässt bis zur Hälfte der Überlebenden mit Langzeitfolgen wie Taubheit und intellektuellen Defiziten, einschliesslich Gedächtnis- und Lernstörungen. Mittels neuer Krankheitsmodelle und nicht-invasive Methoden beabsichtigen wir die Krankheitsmechanismen der Pneumokokken- und Listerien-Meningitis besser zu verstehen und so neue therapeutische Ansätze zu entwickeln.
Lay summary

Einblicke in die Pathophysiologie der Pneumokokken und Listerien Meningitis mittels komplementärer Krankheitsmodelle und nicht-invasive Methoden zur Entwicklung neuer Therapien.

Inhalt und Ziele des Forschungsprojekts

Im Rahmen dieses Projektes fokussieren wir auf Meningitis verursacht durch Streptococcus pneumoniae und Listeria monocytogenes. Mittels neu entwickelter Krankheitsmodelle und Methoden wollen wir ein besseres Bild der Pathophysiologie der Meningitis schaffen. Das  Projekt besteht aus 3 Zielen: 1: Mit der Entwicklung eines Zebrafisch-Modells der Erkrankung und dank der transparenten Farbeigenschaft von Zebrafischembryos, haben wir die Möglichkeit, die Interaktion zwischen Pathogen und Wirt mittels Fluoreszenzmikroskopie über längere Zeit zu verfolgen und zu charakterisieren. Damit erlaubt uns das Zebrafischmodell eine effizientere Suche nach neuen Therapieansätzen um die Folgen der Meningitis auf die Neurointegrative Leistung zu verbessern. 2: Um das aktuelle Rattenmodel für Pneumokokken- und Listerien-Meningitis besser zu charakterisieren, wollen wir auch Methoden etablieren, die das Vorhersagen des neuronalen Schaden und folglich auch der neurofunktionelle Defizite mittels nicht invasiver Methoden erlauben. Zu den Methoden gehören die Messungen des Proteins „Neurofilament“ im Liquor und Serum als Biomarker für Hirn-Schaden sowie bildgebende Verfahren durch Magnetresonanz. 3: Mit den neu entwickelten Methoden haben wir Werkzeuge zur Hand um neue therapeutische Ansätze zu entwickeln und zu evaluieren.

Wissenschaftlicher und gesellschaftlicher Kontext des Forschungsprojekts

Im Rahmen dieses Projekts werden innovative Krankheitsmodelle und nicht-invasive Methoden etabliert um damit neue therapeutische Ansätze für die Behandlung der Pneumokokken und Listerien Meningitis zu entwickeln und zu evaluieren. Die Resultate stehen dann für die Weiterentwicklung in der klinischen Evaluation zur Verfügung.

 


Direct link to Lay Summary Last update: 08.10.2019

Responsible applicant and co-applicants

Employees

Project partner

Associated projects

Number Title Start Funding scheme
162583 Improving the outcome of bacterial meningitis: combination versus single drug adjuvant therapies 01.02.2016 Project funding (Div. I-III)
160780 Viral Plasticity Underlying Tropism And Pathogenesis/ Innate Immune Evasion Of Emerging Viruses 01.11.2015 Sinergia

Abstract

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 diseases 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. We formulated the following 3 aims of a project over 4 years: Aim 1: To establish and characterize experimental models of pneumococcal meningitis and neurolisteriosis in zebrafish embryos. Rodent models of experimental bacterial meningitis do not allow performing large screening for pathophysiologic studies to evaluate pharmacological interventions. Zebrafish embryos have recently emerged as a model to study host-pathogen interactions. By taking advantage of the transparency of the embryos combined with fluorescent labeling of bacteria, it is possible to study host-pathogen interaction in vivo in a non-invasive and therefore longitudinal way. This, combined with the possibility of pharmacological treatment by bath water exposure allows high throughput analysis not feasible in rodent experimental models. We plan to establish the model for both pneumococcal meningitis and listeria meningoencephalitis since both brain infections are associated with severe burden of disease and the feasibility of inducing experimental infections in zebrafish has been demonstrated.Aim 2: To characterize and refine models of pneumococcal and listeric brain infection in rodents by assessing the potential of non-invasive endpoints including neurofilament in cerebrospinal fluid and serum and imaging techniques including 7 Tesla MRI to predict brain damage and subsequent neurofunctional deficits. Over the last two decades, we have developed, characterized and employed experimental models of bacterial meningitis in rodents. In these models, neuronal damage has been quantified by histomorphometry. Through the interference with critical pathophysiological pathways identified in the model we were able to specifically target these mechanisms by therapeutic interventions and thereby succeeded in identifying adjuvant therapies that reduce brain damage and improve neurofunctional outcome. However, by using terminal endpoints the link between neuroprotection by adjuvant therapy and its effect on neurofunctional outcome was indirect, since these parameters had to be evaluated in different cohorts. Here we propose to complement the current rat model of bacterial meningitis with new non-invasive techniques as an index for neuronal damage. By combining these models and techniques, we will be able to gain critical insights into the pathophysiology of invasive bacterial brain infections from the early infectious stage to brain damage and subsequent neurofunctional sequelae. Aim 3: To identify new and effective adjuvant therapies and evaluate their impact on survival, inflammation, neuronal damage and outcome by using the combined methodological approaches described in Aim 1 and Aim 2. The newly developed methodologies will be used for evaluating novel therapeutic strategies with the potential to attenuate inflammation and brain damage in the context of bacterial meningitis.The proposed studies focus on brain injury and neurofunctional deficits induced by the two bacterial pathogens that most frequently cause BM, but we are confident that the results obtained by this approach will also be of interest for other types of pathologies of the brain mediated by infection and immunity.
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