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* Department of Molecular Biology & Biochemistry and Center for Immunology,
Department of Pathology & Laboratory Medicine and Center for Immunology, University of California, Irvine, CA 92697;
Department of Neurology and
Department of Pathology, University of Southern California, Keck School of Medicine, Los Angeles, CA 90033
Using the recombinant murine coronavirus mouse hepatitis virus (MHV) expressing the T cell-chemoattractant CXCL10 (MHV-CXCL10), we demonstrate a potent antiviral role for CXCL10 in host defense. Instillation of MHV-CXCL10 into the CNS of CXCL10-deficient (CXCL10–/–) mice resulted in viral infection and replication in both brain and liver. Expression of virally encoded CXCL10 within the brain protected mice from death and correlated with increased infiltration of T lymphocytes, enhanced IFN-
secretion, and accelerated viral clearance when compared with mice infected with an isogenic control virus, MHV. Similarly, viral clearance from the livers of MHV-CXCL10-infected mice was accelerated in comparison to MHV-infected mice, yet was independent of enhanced infiltration of T lymphocytes and NK cells. Moreover, CXCL10–/– mice infected with MHV-CXCL10 were protected from severe hepatitis as evidenced by reduced pathology and serum alanine aminotransferase levels compared with MHV-infected mice. CXCL10-mediated protection within the liver was not dependent on CXC-chemokine receptor 2 (CXCR2) signaling as anti-CXCR2 treatment of MHV-CXCL10-infected mice did not modulate viral clearance or liver pathology. In contrast, treatment of MHV-CXCL10-infected CXCL10–/– mice with anti-CXCL10 Ab resulted in increased clinical disease correlating with enhanced viral recovery from the brain and liver as well as increased serum alanine aminotransferase levels. These studies highlight that CXCL10 expression promotes protection from coronavirus-induced neurological and liver disease.
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 Grants NS41249 (to T.E.L.) and NS18146 (to S.A.S. and T.E.L.) from the National Institutes of Health and by Grant 3278-A-3 (to T.E.L.) from the National Multiple Sclerosis Society.
2 Current address: Department of Neurosciences, Lerner Research Institute, The Cleveland Clinic Foundation, Cleveland, OH 44195.
3 Address correspondence and reprint requests to Dr. Thomas E. Lane, Department of Molecular Biology & Biochemistry, 3205 McGaugh Hall, University of California, Irvine, CA 92697-3900. E-mail address: tlane{at}uci.edu
4 Abbreviations used in this paper: MHV, mouse hepatitis virus; sALT, serum alanine aminotransferase; i.c., intracranial; p.i., postinfection; ORF, open reading frame.
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  K. B. Walsh, M. B. Lodoen, R. A. Edwards, L. L. Lanier, and T. E. Lane Evidence for Differential Roles for NKG2D Receptor Signaling in Innate Host Defense against Coronavirus-Induced Neurological and Liver Disease J. Virol., March 15, 2008; 82(6): 3021 - 3030. [Abstract] [Full Text] [PDF]
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K. B. Walsh, L. L. Lanier, and T. E. Lane NKG2D Receptor Signaling Enhances Cytolytic Activity by Virus-Specific CD8+ T Cells: Evidence for a Protective Role in Virus-Induced Encephalitis J. Virol., March 15, 2008; 82(6): 3031 - 3044. [Abstract] [Full Text] [PDF]
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