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Updated: Jun 12, 2025
A Murine Model of Dengue Virus-induced Acute Viral Encephalitis-like Disease
Published on: April 28, 2019
GAS6 as a potential target to alleviate neuroinflammation during Japanese encephalitis in mouse models
Peiyu Bian1, Haijun Zhang2, Chuantao Ye3
1Department of Geriatrics, Xijing Hospital, Air Force Medical University, Xi'an, 710027, China.
Abstract:
Viral encephalitis is characterized by inflammation of the brain parenchyma caused by a variety of viruses, among which the Japanese encephalitis (JE) virus (JEV) is a typical representative arbovirus. Neuronal death, neuroinflammation, and breakdown of the blood brain barrier (BBB) constitute vicious circles of JE progression. Currently, there is no effective therapy to prevent this damage. Growth arrest specific gene 6 (GAS6) is a secreted growth factor that binds to the TYRO3, AXL, and MERTK (TAM) family of receptor tyrosine kinases and has been demonstrated to participate in neuroprotection and suppression of inflammation in many central nervous system (CNS) diseases which has great potential for JE intervention. In this study, we found that GAS6 expression in the brain was decreased and was reversely correlated with viral load and neuronal loss. Mice with GAS6/TAM signalling deficiency showed higher mortality and accelerated neuroinflammation during peripheral JEV infection, accompanied by BBB breakdown. GAS6 directly promoted the expression of tight junction proteins in bEnd.3 cells and strengthened BBB integrity, partly via AXL. Mice administered GAS6 were more resistant to JEV infection due to increased BBB integrity, as well as decreased viral load and neuroinflammation. Thus, targeted GAS6 delivery may represent a strategy for the prevention and treatment of JE especially in patients with impaired BBB.
Insights
Growth arrest specific gene 6 (GAS6) protects the brain from Japanese encephalitis virus (JEV) infection by strengthening the blood-brain barrier (BBB). Restoring GAS6 levels reduces neuroinflammation and improves survival in JEV-infected mice.
Area of Science:
- Neuroscience
- Virology
- Immunology
Background:
- Japanese encephalitis (JE) is a severe brain inflammation caused by the Japanese encephalitis virus (JEV).
- Current treatments for JE are ineffective, and disease progression involves neuronal death, neuroinflammation, and blood-brain barrier (BBB) breakdown.
- Growth arrest specific gene 6 (GAS6) is a protein involved in neuroprotection and anti-inflammation in central nervous system (CNS) diseases.
Purpose of the Study:
- To investigate the role of GAS6 in JEV infection and its potential as a therapeutic target.
- To determine the effect of GAS6 on BBB integrity and neuroinflammation during JEV infection.
Main Methods:
- Assessed GAS6 expression levels in the brain and correlated them with viral load and neuronal loss.
- Utilized GAS6/TAM signaling-deficient mice to study JEV infection outcomes.
- Examined the effect of GAS6 on tight junction proteins and BBB integrity in bEnd.3 cells.
- Administered GAS6 to JEV-infected mice to evaluate its protective effects.
Main Results:
- GAS6 expression was decreased in JEV-infected brains and inversely correlated with viral load and neuronal loss.
- Mice lacking GAS6/TAM signaling exhibited increased mortality, accelerated neuroinflammation, and BBB breakdown during JEV infection.
- GAS6 enhanced BBB integrity by promoting tight junction protein expression, partly through AXL signaling.
- GAS6 administration protected mice against JEV infection by improving BBB integrity, reducing viral load, and mitigating neuroinflammation.
Conclusions:
- GAS6 plays a crucial protective role against JEV-induced neuroinflammation and BBB damage.
- Targeted delivery of GAS6 shows promise as a preventative and therapeutic strategy for JE, particularly in cases with compromised BBB integrity.
