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Journal of Virology, November 2002, p. 11688-11703, Vol. 76, No. 22
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.22.11688-11703.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Age-Dependent Resistance to Lethal Alphavirus Encephalitis in Mice: Analysis of Gene Expression in the Central Nervous System and Identification of a Novel Interferon-Inducible Protective Gene, Mouse ISG12

Lucia Labrada,1 Xiao Huan Liang,1 Wei Zheng,2 Christine Johnston,1 and Beth Levine1*

Department of Medicine, Columbia University College of Physicians and Surgeons,1 Department of Biostatistics, Mailman School of Public Health, Columbia University, New York, New York 100322

Received 18 April 2002/ Accepted 6 August 2002

Several different mammalian neurotropic viruses produce an age-dependent encephalitis characterized by more severe disease in younger hosts. To elucidate potential factors that contribute to age-dependent resistance to lethal viral encephalitis, we compared central nervous system (CNS) gene expression in neonatal and weanling mice that were either mock infected or infected intracerebrally with a recombinant strain, dsTE12Q, of the prototype alphavirus Sindbis virus. In 1-day-old mice, infection with dsTE12Q resulted in rapidly fatal disease associated with high CNS viral titers and extensive CNS apoptosis, whereas in 4-week-old mice, dsTE12Q infection resulted in asymptomatic infection with lower CNS virus titers and undetectable CNS apoptosis. GeneChip expression comparisons of mock-infected neonatal and weanling mouse brains revealed developmental regulation of the mRNA expression of numerous genes, including some apoptosis regulatory genes, such as the proapoptotic molecules caspase-3 and TRAF4, which are downregulated during development, and the neuroprotective chemokine, fractalkine, which is upregulated during postnatal development. In parallel with increased neurovirulence and increased viral replication, Sindbis virus infection in 1-day-old mice resulted in both a greater number of host inflammatory genes with altered expression and greater changes in levels of host inflammatory gene expression than infection in 4-week-old mice. Only one inflammatory response gene, an expressed sequence tag similar to human ISG12, increased by a greater magnitude in infected 4-week-old mouse brains than in infected 1-day-old mouse brains. Furthermore, we found that enforced neuronal ISG12 expression results in a significant delay in Sindbis virus-induced death in neonatal mice. Together, our data identify genes that are developmentally regulated in the CNS and genes that are differentially regulated in the brains of different aged mice in response to Sindbis virus infection.

* Corresponding author. Mailing address: Department of Medicine, Columbia University College of Physicians & Surgeons, 630 West 168th St., New York, NY 10032. Phone: (212) 305-7312. Fax: (212) 305-7290. E-mail: levine{at}cuccfa.ccc. columbia.edu.

Journal of Virology, November 2002, p. 11688-11703, Vol. 76, No. 22
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.22.11688-11703.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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