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Astrocyte gp130 Expression Is Critical for the Control of Toxoplasma Encephalitis¹

Katrin Drögemüller^*, Ulrike Helmuth^*, Anna Brunn, Monika Sakowicz-Burkiewicz^*,, David H. Gutmann, Werner Mueller^,¶, Martina Deckert and Dirk Schlüter^2,*

^* Institut für Medizinische Mikrobiologie, Otto-von-Guericke-Universität, Magdeburg, Germany; Abteilung für Neuropathologie, Universität zu Köln, Cologne, Germany; Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110; Helmholtz-Zentrum für Infektionsforschung, Braunschweig, Germany; and ^¶ University of Manchester, Manchester, United Kingdom

Toxoplasma gondii infects astrocytes, neurons and microglia cells in the CNS and, after acute encephalitis, persists within neurons. Robust astrocyte activation is a hallmark of Toxoplasma encephalitis (TE); however, the in vivo function of astrocytes is largely unknown. To study their role in TE we generated C57BL/6 GFAP-Cre gp130^fl/fl mice (where GFAP is glial fibrillary acid protein), which lack gp130, the signal-transducing receptor for IL-6 family cytokines, in their astrocytes. In the TE of wild-type mice, the gp130 ligands IL-6, IL-11, IL-27, LIF, oncostatin M, ciliary neurotrophic factor, B cell stimulating factor, and cardiotrophin-1 were up-regulated. In addition, GFAP⁺ astrocytes of gp130^fl/fl control mice were activated, increased in number, and efficiently restricted inflammatory lesions and parasites, thereby contributing to survival from TE. In contrast, T. gondii- infected GFAP-Cre gp130^fl/fl mice lost GFAP⁺ astrocytes in inflammatory lesions resulting in an inefficient containment of inflammatory lesions, impaired parasite control, and, ultimately, a lethal necrotizing TE. Production of IFN- and the IFN--induced GTPase (IGTP), which mediate parasite control in astrocytes, was even increased in GFAP-Cre gp130^fl/fl mice, indicating that instead of the direct antiparasitic effect the immunoregulatory function of GFAP-Cre gp130^fl/fl astrocytes was disturbed. Correspondingly, in vitro infected GFAP-Cre gp130^fl/fl astrocytes inhibited the growth of T. gondii efficiently after stimulation with IFN-, whereas neighboring noninfected and TNF-stimulated GFAP-Cre gp130^fl/fl astrocytes became apoptotic. Collectively, these are the first experiments demonstrating a crucial function of astrocytes in CNS infection.

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 in part by grants from the Deutsche Forschungsgemeinschaft (Schl. 392/7-1) and the Bundesministerium für Bildung und Forschung (ToxoNet 01; TP1).

² 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

³ Abbreviations used in this paper: TE, Toxoplasma encephalitis; BSF, B cell stimulating factor; CNTF, ciliary neurotrophic factor; GFAP, glial fibrillary acid protein; HPF, high power field; HPRT, hypoxanthine phosphoribosyl transferase; i.c., intracerebral; IGTP, IFN--induced GTPase; iNOS, inducible NO synthase; LDH, lactate dehydrogenase; NeuN, neuron-specific nuclear protein; OSM, oncostatin M; WT, wild type.