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Journal of Virology, September 2006, p. 9082-9092, Vol. 80, No. 18
0022-538X/06/$08.00+0     doi:10.1128/JVI.00795-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Altered Central Nervous System Gene Expression Caused by Congenitally Acquired Persistent Infection with Lymphocytic Choriomeningitis Virus{dagger} ,{ddagger}

Stefan Kunz,1 Jillian M. Rojek,1 Amanda J. Roberts,1 Dorian B. McGavern,1 Michael B. A. Oldstone,1,2 and Juan Carlos de la Torre1*

Molecular and Integrative Neurosciences Department (MIND),1 Department of Infectiology, The Scripps Research Institute, La Jolla, California 920372

Received 18 April 2006/ Accepted 26 June 2006

Neonatal infection of most mouse strains with lymphocytic choriomeningitis virus (LCMV) leads to a life-long persistent infection characterized by high virus loads in the central nervous system (CNS) in the absence of inflammation and tissue destruction. These mice, however, exhibit impaired learning and memory. The occurrence of cognitive defects in the absence of overt CNS pathology led us to the hypothesis that chronic virus infection may contribute to neuronal dysfunction by altering the host's gene expression profile. To test this hypothesis, we examined the impact of LCMV persistence on host gene expression in the CNS. To model the natural route of human congenital CNS infection observed with a variety of viruses, we established a persistently infected mouse colony where the virus was maintained via vertical transmission from infected mothers to offspring (LCMV-cgPi). LCMV-cgPi mice exhibited a lifelong persistent infection involving the CNS; the infection was associated with impaired spatial-temporal learning. Despite high viral loads in neurons of the brains of adult LCMV-cgPi mice, we detected changes in the host's CNS gene expression for only 75 genes, 56 and 19 being significantly induced and reduced, respectively. The majority of the genes induced in the brain of LCMV-cgPi mice were interferon (IFN)-stimulated genes (ISGs) and included the transcription factors STAT1 and IRF9, the ISG15 protease UBP43, and the glucocorticoid attenuated-response genes GARG16 and GARG49. Based on their crucial role in antiviral defense, these ISGs may play an important role in limiting viral spread and replication. However, since IFNs have also been implicated in adverse effects on neuronal function, the chronic induction of some ISGs may also contribute to the observed cognitive impairment.

* Corresponding author. Mailing address: Molecular and Integrative Neurosciences Department (MIND) IMM6, The Scripps Research Institute, 10550 N. Torrey Pines Rd., La Jolla, CA 92037. Phone: (858) 784-9462. Fax: (858) 784-9981. E-mail: juanct{at}scripps.edu.

{dagger} This is publication no. 18119 from the Molecular and Integrative Neurosciences Department (MIND) of the Scripps Research Institute.

{ddagger} Supplemental material for this article may be found at http://jvi.asm.org.

Journal of Virology, September 2006, p. 9082-9092, Vol. 80, No. 18
0022-538X/06/$08.00+0     doi:10.1128/JVI.00795-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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