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Lack of both Fas ligand and perforin protects from flavivirus-mediated encephalitis in mice
Rosa M Licon Luna1, Eva Lee, Arno Müllbacher
1Division of Immunology and Cell Biology, John Curtin School of Medical Research, The Australian National University, Canberra, Australian Capital Territory 2601, Australia.
Abstract:
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.
Insights
Encephalitic flaviviruses invade the brain via crucial cytolytic effector functions. Blocking these pathways, like granule exocytosis or Fas-mediated cytotoxicity, significantly delays or prevents fatal encephalitis in mice.
Area of Science:
- Neurovirology
- Immunology
Background:
- Encephalitic flaviviruses cause life-threatening brain inflammation.
- The precise mechanisms of viral brain entry remain largely unknown.
- Understanding viral neuroinvasion is critical for developing effective treatments.
Purpose of the Study:
- To elucidate the role of cytotoxic effector functions in flavivirus brain entry.
- To investigate the contribution of granule exocytosis and Fas-mediated pathways to viral neuroinvasion.
- To establish a mouse model for studying flavivirus encephalitis.
Main Methods:
- Intravenous administration of encephalitic flavivirus to 6-week-old mice.
- Utilizing genetically modified mice deficient in specific cytotoxic pathways (granule exocytosis, Fas-mediated).
- Monitoring viral load, mortality rates, and disease progression.
Main Results:
- Cytolytic effector functions are crucial for flavivirus invasion into the brain.
- Mice lacking granule exocytosis or Fas-mediated cytotoxicity exhibited delayed and reduced mortality.
- Mice deficient in both pathways were resistant to peripheral viral infection.
Conclusions:
- Cytolytic immune responses play a pivotal role in facilitating flavivirus entry into the central nervous system.
- Targeting these cytotoxic pathways may offer a therapeutic strategy against flavivirus encephalitis.
- This study provides key insights into the pathogenesis of neurotropic flavivirus infections.
