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Impact of Epstein-Barr Virus Nuclear Antigen 1 on Neuroinflammation in PARK2 Knockout Mice
Davide Cossu1,2,3, Yuji Tomizawa1, Sachiko Noda1
1Department of Neurology, Juntendo University, Tokyo 1138431, Japan.
Abstract:
This study aimed to explore the intricate relationship between mitochondrial dysfunction, infection, and neuroinflammation, focusing specifically on the impact of pathogenic epitopes of the Epstein-Barr Virus (EBV) nuclear antigen 1 (EBNA1) in a mouse model of mitochondrial dysfunctions. The investigation included female middle-aged PARK2 and C57BL/6J wild-type mice immunized with EBNA1386-405 or with active experimental autoimmune encephalomyelitis (EAE) induction by the myelin oligodendrocyte glycoprotein (MOG)35-55 peptide. The PARK2 mice developed more severe EAE than the wild-type mice. Following immunization with EBNA1386-405, only PARK2 exhibited symptoms resembling EAE. During the acute phase, PARK2 mice immunized with either MOG35-55 or EBNA1386-405 exhibited a similar infiltration of the T cells and macrophages in the spinal cord and decreased glial fibrillary acidic protein (GFAP) expression in the brain. However, the EBNA1386-405 -immunized PARK2 mice showed significantly increased frequencies of CD8a+ T cells and CD11c+ B cells, and distinct cytokine profiles in the periphery compared to the wild-type controls. These findings highlight the role of EBV in exacerbating inflammation, particularly in the context of mitochondrial deficiencies.
Insights
Mitochondrial dysfunction exacerbates Epstein-Barr Virus (EBV) effects, worsening neuroinflammation and experimental autoimmune encephalomyelitis (EAE) symptoms in PARK2 mice. This highlights EBV
Area of Science:
- Neuroimmunology
- Mitochondrial Biology
- Virology
Background:
- Mitochondrial dysfunction is linked to neuroinflammatory diseases.
- Epstein-Barr Virus (EBV) infection is associated with various neurological conditions.
- The role of specific EBV antigens in neuroinflammation, especially with mitochondrial defects, requires further investigation.
Purpose of the Study:
- To investigate the impact of pathogenic Epstein-Barr Virus nuclear antigen 1 (EBNA1) epitopes on neuroinflammation in a mouse model with mitochondrial dysfunction.
- To compare the effects of EBNA1 immunization and experimental autoimmune encephalomyelitis (EAE) induction in PARK2 mutant mice versus wild-type controls.
Main Methods:
- Utilized female middle-aged PARK2 mutant and C57BL/6J wild-type mice.
- Immunized mice with EBNA1386-405 peptide or induced EAE using myelin oligodendrocyte glycoprotein (MOG)35-55 peptide.
- Assessed clinical EAE scores, spinal cord immune cell infiltration (T cells, macrophages), brain glial fibrillary acidic protein (GFAP) expression, peripheral immune cell frequencies (CD8a+ T cells, CD11c+ B cells), and cytokine profiles.
Main Results:
- PARK2 mice exhibited more severe EAE than wild-type mice.
- Mice immunized with EBNA1386-405 developed EAE-like symptoms specifically in the PARK2 group.
- Both MOG35-55 and EBNA1386-405 induced similar spinal cord immune cell infiltration and decreased brain GFAP in PARK2 mice during acute EAE.
- EBNA1386-405-immunized PARK2 mice showed increased CD8a+ T cells, CD11c+ B cells, and distinct peripheral cytokine profiles compared to controls.
Conclusions:
- Mitochondrial dysfunction, specifically in PARK2 mice, exacerbates neuroinflammation and EAE severity.
- EBV EBNA1 epitopes can trigger EAE-like symptoms in the context of mitochondrial defects.
- These findings underscore the critical role of EBV in potentiating inflammatory responses, particularly when mitochondrial pathways are compromised.
