Neuroinfectiology

Leiter / Heads

Prof. Dr. med. Uwe KÖDEL

Univ.Prof. Dr. med. Hans-Walter PFISTER

PD Dr. med. Matthias KLEIN

Research topics

The “Neuroinfectious Diseases Research Group” has a long-term experience in investigating the pathomechanisms of neuroinfectious diseases with two main focuses: bacterial meningitis and neuroborreliosis. Over the past years, our group has identified central mechanisms of immune regulation in the cerebrospinal fluid (CSF) space and meningitis-related brain and cochlear damage (using different in vitro and in vivo approaches). We demonstrated that, in the CSF, the presence of pneumococci is recognized initially by the concerted action of several Toll-like receptors such as TLR2 and TLR4. Consequently, TLR signaling via MyD88 results in the activation of transcription factors like NF-kappaB which regulate the production of inflammatory factors like interleukin (IL)-1. Released IL-1 enhances MyD88-dependent NF-kappa B activation via a positive feedback loop involving IL-1 family receptors. The biological activity of IL-1 seems to be essential for neutrophil infitration into the CSF. The neutrophils, in turn, substantially contribute to meningitis-induced brain tissue damage (via releasing cytotoxic molecules like peroxynitrite and proteolytic enzymes). Another focus of our group lies on the proteomic analysis of the host immune response in the CSF. Through protein expression profiling we have for instance identified an up-regulation of the chemokines CXCL-16 and CCL-20 during acute pneumococcal meningitis in humans and mice. By using gene-deficient mice and neutralizing antibodies, we showed a novel function of these chemokines in bacterial infections, namely their contribution to the recruitment of neutrophils to sites of infections. Moreover, we have identified substantially increased levels of CXCL13 in the CSF of patients with neuroborreliosis. A prospective clinical study, conducted by our group in cooperation with the Department of Clinical Chemistry at the Klinikum Grosshadern, suggests that CXCL13 is a promising additional diagnostic and therapeutic marker for neuroborreliosis. Noteworthily, elevated concentrations of CXCL13 were also detected in CSF samples obtained from patients with CNS lymphoma and carcinomatous meningitis. Recently, we finished another prospective clinical trial which was done in cooperation with the Neurooncology Study Group at our hospital and focussed on the potential role of CXCL13 as a biomarker of these diseases.

Cooperations with:

• Department Genetics of Microorganisms, Ernst Moritz Arndt University Greifswald (Prof. Dr. Sven Hammerschmidt)
• Insitute of Medical Microbiology, University of Duisburg-Essen (Prof. Dr. Carsten Kirschning)
• Competence Center – Functional Genomics, Ernst Moritz Arndt University Greifswald (Dr. Frank Schmidt)
• Department of Neurology, Amsterdam Medical Center (Prof. D. van de Beek, Dr. Matthijs Brouwer)
• UOC Batteriologia, Azienda Ospedaliera Universitaria Senese (Frau Dr. Susanna Ricci)
• European Study Group for Infectious Diseases of the Brain (an official ESCMID study group)
• Institute for Experimental Immunology, University of Zürich (Prof. Dr. Adriano Fontana)
• National Reference Center for Borrelia, Bavarian Health and Food Safety Authority (LGL; Dr. Volker Fingerle)
• Neurooncology Study Group of the Department of Neurology, LMU Munich (Prof. Dr. Andreas Straube, PD Dr. Louisa von Baumgarten)
• Center for Neuropathology of the LMU Munich (Prof. Dr. Armin Giese)
• Institute of Laboratory Medicine of the LMU Munich (Dr. Manfred Wick)

Selected publications:

• Thaler FS, Laurent SA, Huber M, Mulazzani M, Dreyling M, Ködel U, Kümpfel T, Straube A, Meinl E, von Baumgarten L. Soluble TACI and soluble BCMA as biomarkers in primary central nervous system lymphoma. Neuro Oncol. 2017;19:1618-1627.
• Masouris I, Klein M, Dyckhoff S, Angele B, Pfister HW, Koedel U. Inhibition of DAMP signaling as an effective adjunctive treatment strategy in pneumococcal meningitis. J Neuroinflammation. 2017;14:214.
• Bewersdorf JP, Grandgirard D, Koedel U, Leib SL. Novel and preclinical treatment strategies in pneumococcal meningitis. Curr Opin Infect Dis. 2017 [Epub ahead of print]
• Zierhut M, Dyckhoff S, Masouris I, Klein M, Hammerschmidt S, Pfister HW, Ayata K, Idzko M, Koedel U. Role of purinergic signaling in experimental pneumococcal meningitis. Sci Rep. 2017;7:44625.
• Koedel U, Pfister HW. Lyme neuroborreliosis. Curr Opin Infect Dis. 2017;30:101-107.
• Buchholz G, Koedel U, Pfister HW, Kastenbauer S, Klein M. Dramatic reduction of mortality in pneumococcal meningitis. Crit Care 2016;20:312.
• Van de Beek D, Brouwer M, Hasbun R, Koedel U, Whitney CG, Wijdicks E. Community-acquired bacterial meningitis. Nat Rev Dis Primers 2016;2:16074.
• Koedel U, Pfister HW. Lyme neuroborreliosis. Curr Opin Infect Dis 2016.
• van de Beek D, Cabellos C, Dzupova O, Esposito S, Klein M, Kloek AT, Leib SL, Mourvillier B, Ostergaard C, Pagliano P, Pfister HW, Read RC, Sipahi OR, Brouwer MC; ESCMID Study Group for Infections of the Brain (ESGIB). ESCMID guideline: diagnosis and treatment of acute bacterial meningitis. Clin Microbiol Infect. 2016 May;22 Suppl 3:S37-62.
• Klein M, Bühler R, Eiffert H, Grabein B, Linn J, Nau R, Salzberger B, Tumani H, Weber JR, Pfister HW. Ambulant erworbene bakterielle (eitrige) Meningoenzephalitis im Erwachsenenalter. Akt Neurol 2016; 43(06): 358-368.
• Koedel U, Fingerle V, Pfister HW. Lyme neuroborreliosis-epidemiology, diagnosis and management. Nat Rev Neurol 2015;11:446-56.
• Wache C, Klein M, Ostergaard C, et al. Myeloid-Related Protein 14 Promotes Inflammation and Injury in Meningitis. J Infect Dis 2015; 212:247-57.
• Brouwer MC, Meijers JC, Baas F, et al. Plasminogen activator inhibitor-1 influences cerebrovascular complications and death in pneumococcal meningitis. Acta Neuropathol 2013;127:553-64.
• Höhne C, Wenzel M, Angele B, et al. High mobility group box 1 prolongs inflammation and worsens disease in pneumococcal meningitis. Brain 2013;136:1746-59.
• Oldenburg M, Kruger A, Ferstl R, et al. TLR13 Recognizes Bacterial 23S rRNA Devoid of Erythromycin Resistance-Forming Modification. Science 2012;337:1111-5.
• Klein M, Koedel U, Pfefferkorn T, Zeller G, Woehrl B, Pfister HW. Arterial cerebrovascular complications in 94 adults with acute bacterial meningitis. Crit Care 2011;15:R281.
• Woehrl B, Brouwer MC, Murr C, et al. Complement component 5 contributes to poor disease outcome in humans and mice with pneumococcal meningitis. J Clin Invest 2011;121:3943-53.
• Schmidt C, Plate A, Angele B, et al. A prospective study on the role of CXCL13 in Lyme neuroborreliosis. Neurology 2011;76:1051-8.

Förderung/Funding

e.g. Deutsche Forschungsgemeinschaft, Else-Kröner-Fresenius-Stiftung, BMBF, FöFoLe-Programm der Universität München