Lack of both Fas ligand and perforin protects from flavivirus-mediated encephalitis in mice.
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 10(5) PFU of virus gave mortality in approximately 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.
Licon Luna
Rosa M
RM
Division of Immunology and Cell Biology, John Curtin School of Medical Research, The Australian National University, Canberra, Australian Capital Territory 2601, Australia.
Lee
Eva
E
Müllbacher
Arno
A
Blanden
Robert V
RV
Langman
Rod
R
Lobigs
Mario
M
D000818:Animals; D001921:Brain / Q000821:virology; D002460:Cell Line; D004195:Disease Models, Animal; D018068:Encephalitis Virus, Murray Valley; D004671:Encephalitis, Arbovirus / Q000276:immunology* / Q000821:virology; D053222:Fas Ligand Protein; D018178:Flaviviridae Infections / Q000276:immunology* / Q000821:virology; D008562:Membrane Glycoproteins / Q000172:deficiency* / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D019014:fas Receptor / Q000235:genetics / Q000502:physiology*
D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D019014:fas Receptor; D054353:Perforin