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Characterization of the inflammatory response during acute measles encephalitis in NSE-CD46 transgenic mice
M Manchester1, D S Eto, M B Oldstone
1Department of Neuropharmacology, The Scripps Research Institute, La Jolla, CA 92037, USA. marim@scripps.edu
Abstract:
Expression of the human measles virus receptor, CD46, in the murine central nervous system allows infection and replication by wild-type human measles virus (MV) strains (Rall, G.F., Manchester, M., Daniels L.R., Callahan, E., Belman, A., Oldstone, M.B.A., 1997. A transgenic mouse model for measles virus infection of the brain. Proc. Natl. Acad. Sci. U.S.A. 94, 2243-2248). MV replicates in neurons in focal lesions of the cortex, hippocampus and thalamus, leading to death of the animals. In MV-infected CD46 transgenic mice, infiltration of CD4+ and CD8+ T-lymphocytes, B-lymphocytes and macrophages was seen. Upregulation of MHC class I and class II molecules was observed, along with reactive astrocytosis and microgliosis. Increased chemokine mRNAs, especially RANTES and IP-10, and cytokine RNAs IL-6, TNF-alpha, and IL1-beta were observed. Apoptosis of neurons also was increased. No MV replication or inflammation was seen in similarly inoculated nontransgenic littermates. These results further characterize the MV-induced encephalitis in CD46 transgenic mice and highlight similarities to MV infection of the human CNS.
Insights
Transgenic mice expressing the human measles virus (MV) receptor CD46 in the brain allow MV infection, causing encephalitis and death. This model mimics human measles virus central nervous system infections.
Area of Science:
- Neuroscience
- Virology
- Immunology
Background:
- Measles virus (MV) infection of the central nervous system (CNS) can cause severe neurological disease.
- CD46 is the primary receptor for wild-type MV strains.
- A CD46 transgenic mouse model allows for the study of MV neurotropism and pathogenesis.
Purpose of the Study:
- To characterize the neuropathogenesis of wild-type MV infection in CD46 transgenic mice.
- To investigate the inflammatory and cellular responses in the CNS following MV infection.
- To establish a relevant animal model for human MV encephalitis.
Main Methods:
- Generation of CD46 transgenic mice.
- Intracranial inoculation of wild-type MV.
- Histopathological analysis of brain tissue.
- Immunohistochemistry and molecular analysis of inflammatory markers.
Main Results:
- MV replicated in neurons within focal lesions in the cortex, hippocampus, and thalamus, leading to animal death.
- Infiltration of immune cells (T-lymphocytes, B-lymphocytes, macrophages) and upregulation of MHC molecules were observed.
- Increased expression of chemokines (RANTES, IP-10) and cytokines (IL-6, TNF-alpha, IL1-beta) and neuronal apoptosis were noted.
- No MV replication or inflammation occurred in non-transgenic littermates.
Conclusions:
- CD46 transgenic mice provide a valuable model for studying MV-induced encephalitis.
- The observed pathology and immune response closely resemble human MV CNS infections.
- This model aids in understanding the mechanisms of measles virus neuroinflammation and neuronal damage.