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Journal of Virology, September 2008, p. 8978-8985, Vol. 82, No. 18
0022-538X/08/$08.00+0     doi:10.1128/JVI.00314-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Matrix Metalloproteinase 9 Facilitates West Nile Virus Entry into the Brain{triangledown}

Penghua Wang,1 Jianfeng Dai,1 Fengwei Bai,1 Kok-Fai Kong,2 Susan J. Wong,4 Ruth R. Montgomery,2 Joseph A. Madri,3 and Erol Fikrig1*

Section of Infectious Diseases,1 Section of Rheumatology, Department of Internal Medicine,2 Department of Pathology, Yale University School of Medicine, New Haven, Connecticut 06520,3 Diagnostic Immunology Laboratory, Wadsworth Center, New York State Department of Health, Albany, New York 122014

Received 12 February 2008/ Accepted 3 July 2008

West Nile virus (WNV) is the most-common cause of mosquito-borne encephalitis in the United States. Invasion of the brain by WNV is influenced by viral and host factors, and the molecular mechanism underlying disruption of the blood-brain barrier is likely multifactorial. Here we show that matrix metalloproteinase 9 (MMP9) is involved in WNV entry into the brain by enhancing blood-brain barrier permeability. Murine MMP9 expression was induced in the circulation shortly after WNV infection, and the protein levels remained high even when viremia subsided. In the murine brain, MMP9 expression and its enzymatic activity were upregulated and MMP9 was shown to partly localize to the blood vessels. Interestingly, we also found that cerebrospinal fluid from patients suffering from WNV contained increased MMP9 levels. The peripheral viremia and expression of host cytokines were not altered in MMP9–/– mice; however, these animals were protected from lethal WNV challenge. The resistance of MMP9–/– mice to WNV infection correlated with an intact blood-brain barrier since immunoglobulin G, Evans blue leakage into brain, and type IV collagen degradation were markedly reduced in the MMP9–/– mice compared with their levels in controls. Consistent with this, the brain viral loads, selected inflammatory cytokines, and leukocyte infiltrates were significantly reduced in the MMP9–/– mice compared to their levels in wild-type mice. These data suggest that MMP9 plays a role in mediating WNV entry into the central nervous system and that strategies to interrupt this process may influence the course of West Nile encephalitis.

* Corresponding author. Mailing address: Section of Infectious Diseases, Department of Internal Medicine, Yale University School of Medicine, The Anlyan Center for Medical Research Room S525A, 300 Cedar Street, New Haven, CT 06520-8031. Phone: (203) 785-2453. Fax: (203) 785-3864. E-mail: erol.fikrig{at}yale.edu

{triangledown} Published ahead of print on 16 July 2008.

Journal of Virology, September 2008, p. 8978-8985, Vol. 82, No. 18
0022-538X/08/$08.00+0     doi:10.1128/JVI.00314-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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