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Productive measles virus brain infection and apoptosis in CD46 transgenic mice
A Evlashev1, E Moyse, H Valentin
1INSERM U503, Immunobiologie Fondamentale et Clinique, ENS de Lyon, Lyon, France.
Abstract:
Measles virus (MV) infection causes acute childhood disease, associated in certain cases with infection of the central nervous system (CNS) and development of neurological disease. To develop a murine model of MV-induced pathology, we generated several lines of transgenic mice ubiquitously expressing as the MV receptor a human CD46 molecule with either a Cyt1 or Cyt2 cytoplasmic tail. All transgenic lines expressed CD46 protein in the brain. Newborn transgenic mice, in contrast to nontransgenic controls, were highly sensitive to intracerebral infection by the MV Edmonston strain. Signs of clinical illness (lack of mobility, tremors, and weight loss) appeared within 5 to 7 days after infection, followed by seizures, paralysis, and death of the infected animals. Virus replication was detected in neurons from infected mice, and virus was reproducibly isolated from transgenic brain tissue. MV-induced apoptosis observed in different brain regions preceded the death of infected animals. Similar results were obtained with mice expressing either a Cyt1 or Cyt2 cytoplasmic tail, demonstrating the ability of different isoforms of CD46 to function as MV receptors in vivo. In addition, maternally transferred immunity delayed death of offspring given a lethal dose of MV. These results document a novel CD46 transgenic murine model where MV neuronal infection is associated with the production of infectious virus, similarly to progressive infectious measles encephalitis seen in immunocompromised patients, and provide a new means to study pathogenesis of MV infection in the CNS.
Insights
Researchers developed a new mouse model for measles virus (MV) infection. This model shows how MV affects the central nervous system (CNS), aiding research into measles-related neurological diseases.
Area of Science:
- Virology
- Neuroscience
- Immunology
Background:
- Measles virus (MV) infection can lead to severe central nervous system (CNS) disease.
- Existing models do not fully replicate MV-induced neurological pathology.
- Understanding MV's CNS pathogenesis requires effective animal models.
Purpose of the Study:
- To create a transgenic mouse model for studying MV-induced CNS pathology.
- To investigate the role of human CD46 as a measles virus receptor in vivo.
- To explore MV pathogenesis in the CNS using a novel murine system.
Main Methods:
- Generated transgenic mice expressing human CD46 (Cyt1 or Cyt2 tails) as the MV receptor.
- Assessed susceptibility to intracerebral MV Edmonston strain infection in newborn transgenic mice.
- Monitored clinical signs, viral replication in neurons, apoptosis, and virus isolation from brain tissue.
Main Results:
- Transgenic mice showed high sensitivity to intracerebral MV infection, developing neurological symptoms and death.
- MV replicated in neurons, and infectious virus was isolated from the brains of infected mice.
- MV-induced apoptosis was observed in brain regions preceding animal death; CD46 isoforms effectively served as MV receptors.
Conclusions:
- A novel CD46 transgenic mouse model accurately recapitulates MV neuronal infection and CNS pathology.
- This model mimics aspects of progressive infectious measles encephalitis seen in immunocompromised patients.
- The model provides a valuable tool for investigating MV pathogenesis in the CNS and developing therapeutic strategies.