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Please tell us about your educational background and early research experiences.

I studied Medicine, Sociology, and Philosophy at Georg-August University in Göttingen. For my doctoral thesis, I spent two years at Ulrich Kuhnt's lab at the Department of Neurobiology, Max-Planck Institute for Biophysical Chemistry, Göttingen.

Ulrich Kuhnt and Otto D. Creutzfeldt, head of this department, were very liberal supervisors generating a creative atmosphere. Doctorands had a lot of freedom, as long as they were really interested in science, and the working conditions were excellent. The attitude towards science in this department has had a strong impact on me and on how I organize my research group.

What first drew your interest to meningitis?

During my clinical training, I worked for several years at the Intensive Care Ward of the Department of Neurology at Georg-August University, Göttingen. For a young clinician, bacterial meningitis is a fascinating disease. To do the right things quickly is very important for a good outcome. Nevertheless, some patients die or stay severely impaired, although you did everything right and as quickly as possible.

"Now is the time to critically evaluate the evidence for these approaches to reduce mortality and neuronal injury in meningitis derived from animal experiments and then conduct appropriate clinical trials in patients."

In the first years, my clinical supervisor Hilmar Prange and I, together with several co-workers, studied the entry of antibiotics and osmotherapeutics into the cerebrospinal fluid (CSF) in patients, aiming at improving the treatment of nosocomial central nervous system (CNS) infections and of brain edema. I am happy that the osmotic agent glycerol, whose pharmacokinetics in serum and CSF we also studied, has now been shown in a randomized clinical trial conducted by Heikki Peltola, to effectively improve outcome of bacterial meningitis in children.

When I had passed my exam as a neurologist, I felt that I should go into more basic clinical science. For this reason, I joined Martin Täuber's group at the Division of Infectious Diseases, University of California, San Francisco. There I spent a very productive fellowship which afterwards encouraged me to launch a research group on CNS infections.

Back in Göttingen, a long and fruitful cooperation with the neuropathologist Wolfgang Brück and the microbiologist Helmut Eiffert enabled me to study morphological and molecular aspects of meningitis.

On this occasion I wish to take the opportunity to thank all co-workers, doctorands and post-doctorands for the great time I have had the privilege to spend with them.

One of your highly cited original papers in our analysis is the 2001 Acta Neuropathologica paper written with several coauthors, "A mouse model of Streptococcus pneumoniae meningitis mimicking several features of human disease." Would you tell us about the research behind this paper?

This was not our first paper on the mouse model of bacterial meningitis. Our first paper with this model was published in 1999 in the Journal of Infectious Diseases, and described for the first time the beneficial effect of a bactericidal non-bacteriolytic antibiotic (rifampin) compared to standard therapy with a beta-lactam antibiotic in bacterial meningitis.

The strength of the 2001 paper is the detailed description of the model (e.g., time course of bacterial titers, clinical symptoms, mortality, and histology) which helps others to design experiments with this model addressing their own questions. This mouse model is suitable for therapeutic studies and for the investigation of inflammation in knockout and transgenic mice.

Inoculation of bacteria into the frontal neocortex or subarachnoid space instead of the Cisterna magna and the determination of bacterial titers in cerebellar tissue and not in the CSF are both convenient methods now used by several other groups.

Many of your papers deal with experimental meningitis-what would you say are the key things you've learned about meningitis from these models over the years?

From the work of others and of our group I learned that:

• long-term neuropsychological deficits can be detected in animal models of bacterial meningitis,
• the time window for an effective neuroprotective approach is short (i.e., when treatment starts very early, outcome is good, as long as the antibiotic is bactericidal, when treatment starts too late, outcome is bad, whatever you do),
• antibiotic concentrations in CSF of approximately 10x the minimal inhibitory concentration of the respective pathogen are necessary to produce a maximum bactericidal effect,
• several approaches reducing the concentrations of proinflammatory and/or neurotoxic bacterial products in the CSF are effective, and
• the defense of the brain against invading pathogens is not as weak as previously thought.

Earlier this year, your group published a paper in Infection and Immunity, "Toll-Like Receptor Stimulation Enhances Phagocytosis and Intracellular Killing of Nonencapsulated and Encapsulated Streptococcus pneumoniae by Murine Microglia." Please tell us about your methods and findings in this work. What are the implications for meningitis?

"...the defense of the brain against invading pathogens is not as weak as previously thought."

When you look at histological sections of humans and experimental animals with bacterial meningitis, it is striking how rarely bacteria are seen in the brain parenchyma, although the subarachnoid space is full of bacteria. Moreover, bacterial CNS infections are rare events, although bacteremia is frequent and the brain is considered an immunocompromised site.

Both observations suggest that the defense of the brain against infections is not as insufficient as previously thought. On the other hand, the risk of elderly and immunocompromised persons to develop meningitis and brain abscess is increased.

Our in-vitro work with murine microglial cells shows that microglia are able to ingest and kill even encapsulated bacteria, and that both microglial functions can be stimulated by Toll-like receptor agonists. We hope that this work will end up with a therapeutic approach which helps to protect the brain from invading pathogens. We will work with immunocompromised mice in order to assess whether the resistance of the brain against infections can be increased by priming microglial cells with TLR agonists.

How much have we learned about meningitis in the past decade? What advances would you like to see in the future of meningitis research?

A recently published meta-analysis in Lancet Neurology showed that adjunctive dexamethasone for bacterial meningitis does not seem to significantly reduce death or neurological disability. Since in an early paper from 1996 we saw an increase of neuronal injury in the hippocampal formation in experimental rabbits with S. pneumoniae meningitis, I always was reluctant to truly recommend dexamethasone. We have been using it in the treatment of our patients, because we adhere to the national and international guidelines.

In the past decade a variety of neuroprotective concepts have been shown to be effective in animal models of bacterial meningitis. Now is the time to critically evaluate the evidence for these approaches to reduce mortality and neuronal injury in meningitis derived from animal experiments and then conduct appropriate clinical trials in patients.

Strong candidates are the osmodiuretic glycerol, the free radical scavenger acetylcysteine, and bactericidal non-bacteriolytic antibiotics. Glycerol has already proven effective in infants and children. As a consequence of our experimental work, I favor a randomized trial starting therapy with the bactericidal non-bacteriolytic antibiotic rifampin and adding ceftriaxone one hour later versus standard therapy with ceftriaxone plus ampicillin.

Roland Nau, M.D., MSc
Department of Geriatrics
Evangelisches Krankenhaus Göttingen-Weende
and
Department of Neuropathology
Georg-August University Göttingen
Göttingen, Germany

KEYWORDS: BACTERIAL MENINGITIS, ANTIBIOTICS, OSMOTHERAPEUTICS, CEREBROSPINAL FLUID, CENTRAL NERVOUS SYSTEM, BRAIN EDEMA, GLYCEROL, CHILDREN, MORPHOLOGY, MOUSE MODEL, BACTERIAL TITERS, CEREBELLAR TISSUE, INFLAMMATION, NEUROPSYCHOLOGICAL DEFICITS, MICROGLIA, TOLL-LIKE RECEPTORS, TLR AGONISTS, DEXAMETHASONE, NEUROPROTECTION.

Citing URL: http://sciencewatch.com/ana/st/men/10julSTMenNau/

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