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* Institut für Medizinische Mikrobiologie und Hygiene, Fakultät für klinische Medizin Mannheim der Universität Heidelberg, Mannheim, Germany;
Abteilung für Neuropathologie, Universität zu Köln, Köln, Germany;
Department of Microbiology, School of Medicine, University of Pennsylvania, Philadelphia, PA 19104;
Comparative Genomics Center, School of Veterinary and Biomedical Science/School of Pharmacy and Molecular Sciences, James Cook University, Townsville, Queensland, Australia;
¶ Eli Lilly, Indianapolis, IN 46285; and
|| Institut für Medizinische Mikrobiologie, Otto-von-Guericke Universität Magdeburg, Magdeburg, Germany
Cerebral listeriosis is a life-threatening disease. However, little is known about the bacterial virulence factors responsible for the severe course of disease and the factors of the immune system contributing to the control of Listeria monocytogenes (LM) or even to the damage of the brain. To analyze the importance of the actA gene of LM, which mediates cell-to-cell spread of intracellular LM, the function of TNF in murine cerebral listeriosis was studied. C57BL/6 mice survived an intracerebral (i.c.) infection with actA-deficient LM, but succumbed to infection with wild-type (WT) LM. Upon infection with actA-deficient LM, macrophages and microglial cells rapidly, and later LM-specific CD4 and CD8 T cells, produced TNF. In contrast to WT mice, TNF-deficient animals succumbed to the infection within 4 days due to failure of control of LM. Histology identified a more severe meningoencephalitis, brain edema, and neuronal damage, but a reduced inducible NO synthase expression in TNF-deficient mice. Reciprocal bone marrow chimeras between WT and TNF-deficient mice revealed that hematogenously derived TNF was essential for survival, whereas TNF produced by brain-resident cells was less important. Death of TNF-deficient mice could be prevented by LM-specific T cells induced by an active immunization before i.c. infection. However, brain pathology and inflammation of immunized TNF-deficient mice were still more severe. In conclusion, these findings identify a crucial role of TNF for the i.c. control of LM and survival of cerebral listeriosis, whereas TNF was not responsible for the destruction of brain tissue.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by the Deutsche Forschungsgemeinschaft (Grant No. Schl 392/3-3, to D.S.).
2 Current address: Abteilung für Klinische Chemie und Molekulare Diagnostik, Biomedizinisches Forschungszentrum, Universität Marburg, Marburg, Germany.
3 Current address: Philip Morris Research Laboratories, Köln, Germany.
4 Current address: Klinische Kooperationseinheit für Dermatoonkologie des Deutschen Krebsforschungszentrums, Klinik für Dermatologie, Allergologie und Venerologie, Universitätsklinikum, Mannheim, Germany.
5 Current address: Vaccine Research Center, National Institutes of Health/National Institute of Allergy and Infectious Diseases, Bethesda, MD 20897-3013.
6 Address correspondence and reprint requests to Dr. Dirk Schlüter, Institut für Medizinische Mikrobiologie, Otto-von-Guericke Universität Magdeburg, Leipziger Strasse 44, 39120 Magdeburg, Germany. E-mail address: dirk.schlueter{at}medizin.uni-magdeburg.de
7 Abbreviations used in this paper: LM, Listeria monocytogenes; ActaA, actin polymerase A; WT, wild type; i.c., intracerebral; C-SF, cerebrospinal fluid; p.i., postinfection; LLO, listeriolysin O; iNOS, inducible NO synthase.
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