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Journal of Virology, November 2001, p. 10431-10445, Vol. 75, No. 21
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.21.10431-10445.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Identification of Genes Involved in the Host Response to Neurovirulent Alphavirus Infection

Christine Johnston,1 Wenxia Jiang,1 Tearina Chu,2,dagger and Beth Levine1,*

Department of Medicine, Columbia University College of Physicians & Surgeons, New York, New York 10032,1 and Liver Research Center, Albert Einstein College of Medicine, Bronx, New York 104612

Received 20 February 2001/Accepted 24 July 2001

Single-amino-acid mutations in Sindbis virus proteins can convert clinically silent encephalitis into uniformly lethal disease. However, little is known about the host gene response during avirulent and virulent central nervous system (CNS) infections. To identify candidate host genes that modulate alphavirus neurovirulence, we utilized GeneChip Expression analysis to compare CNS gene expression in mice infected with two strains of Sindbis virus that differ by one amino acid in the E2 envelope glycoprotein. Infection with Sindbis virus, dsTE12H (E2-55 HIS), resulted in 100% mortality in 10-day-old mice, whereas no disease was observed in mice infected with dsTE12Q (E2-55 GLN). dsTE12H, compared with dsTE12Q, replicated to higher titers in mouse brain and induced more CNS apoptosis. Infection with the neurovirulent dsTE12H strain was associated with both a greater number of host genes with increased expression and greater changes in levels of host gene expression than was infection with the nonvirulent dsTE12Q strain. In particular, dsTE12H infection resulted in greater increases in the levels of mRNAs encoding chemokines, proteins involved in antigen presentation and protein degradation, complement proteins, interferon-regulated proteins, and mitochondrial proteins. At least some of these increases may be beneficial for the host, as evidenced by the demonstration that enforced expression of the antiapoptotic mitochondrial protein peripheral benzodiazepine receptor (PBR) protects neonatal mice against lethal Sindbis virus infection. Thus, our findings identify specific host genes that may play a role in the host protective or pathologic response to neurovirulent Sindbis virus infection.

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

dagger Present address: Department of Biochemistry and Molecular Biology, Mount Sinai School of Medicine, New York, NY 10029.

Journal of Virology, November 2001, p. 10431-10445, Vol. 75, No. 21
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.21.10431-10445.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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