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Journal of Virology, January 2006, p. 119-129, Vol. 80, No. 1
0022-538X/06/$08.00+0     doi:10.1128/JVI.80.1.119-129.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

CD8+ T Cells Require Perforin To Clear West Nile Virus from Infected Neurons

Bimmi Shrestha,1 Melanie A. Samuel,2 and Michael S. Diamond1,2,3*

Departments of Medicine,1 Molecular Microbiology,2 Pathology & Immunology, Washington University School of Medicine, St. Louis, Missouri3

Received 8 August 2005/ Accepted 5 October 2005

Injury to neurons after West Nile virus (WNV) infection is believed to occur because of viral and host immune-mediated effects. Previously, we demonstrated that CD8+ T cells are required for the resolution of WNV infection in the central nervous system (CNS). CD8+ T cells can control infection by producing antiviral cytokines (e.g., gamma interferon or tumor necrosis factor alpha) or by triggering death of infected cells through perforin- or Fas ligand-dependent pathways. Here, we directly evaluated the role of perforin in controlling infection of a lineage I New York isolate of WNV in mice. A genetic deficiency of perforin molecules resulted in higher viral burden in the CNS and increased mortality after WNV infection. In the few perforin-deficient mice that survived initial challenge, viral persistence was observed in the CNS for several weeks. CD8+ T cells required perforin to control WNV infection as adoptive transfer of WNV-primed wild-type but not perforin-deficient CD8+ T cells greatly reduced infection in the brain and spinal cord and enhanced survival of CD8-deficient mice. Analogous results were obtained when wild-type or perforin-deficient CD8+ T cells were added to congenic primary cortical neuron cultures. Taken together, our data suggest that despite the risk of immunopathogenesis, CD8+ T cells use a perforin-dependent mechanism to clear WNV from infected neurons.

* Corresponding author. Mailing address: Departments of Medicine, Molecular Microbiology, Pathology & Immunology, Washington University School of Medicine, 660 South Euclid Ave., Box 8051, St. Louis, MO 63110. Phone: (314) 362-2842. Fax: (314) 362-9230. E-mail: diamond{at}borcim.wustl.edu.

Journal of Virology, January 2006, p. 119-129, Vol. 80, No. 1
0022-538X/06/$08.00+0     doi:10.1128/JVI.80.1.119-129.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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