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Journal of Virology, April 2002, p. 3202-3211, Vol. 76, No. 7
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.7.3202-3211.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Lack of both Fas Ligand and Perforin Protects from Flavivirus-Mediated Encephalitis in Mice

Rosa M. Licon Luna,1 Eva Lee,1 Arno Müllbacher,1 Robert V. Blanden,1 Rod Langman,2 and Mario Lobigs1*

Division of Immunology and Cell Biology, John Curtin School of Medical Research, The Australian National University, Canberra, Australian Capital Territory 2601, Australia,1 Conceptual Immunology Group, The Salk Institute, La Jolla, California2

Received 5 September 2001/ Accepted 2 January 2002

The mechanism by which encephalitic flaviviruses enter the brain to inflict a life-threatening encephalomyelitis in a small percentage of infected individuals is obscure. We investigated this issue in a mouse model for flavivirus encephalitis in which the virus was administered to 6-week-old animals by the intravenous route, analogous to the portal of entry in natural infections, using a virus dose in the range experienced following the bite of an infectious mosquito. In this model, infection with 0.1 to 105 PFU of virus gave mortality in ~50% of animals despite low or undetectable virus growth in extraneural tissues. We show that the cytolytic effector functions play a crucial role in invasion of the encephalitic flavivirus into the brain. Mice deficient in either the granule exocytosis- or Fas-mediated pathway of cytotoxicity showed delayed and reduced mortality. Mice deficient in both cytotoxic effector functions were resistant to a low-dose peripheral infection with the neurotropic virus.

* Corresponding author. Mailing address: Division of Immunology and Cell Biology, John Curtin School of Medical Research, The Australian National University, P.O. Box 334, Canberra, A.C.T. 2601, Australia. Phone: (61)-2-6125 4048. Fax: (61)-2-6125 2595. E-mail: Mario.Lobigs{at}anu.edu.au.

Journal of Virology, April 2002, p. 3202-3211, Vol. 76, No. 7
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.7.3202-3211.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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