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Measles virus spread and pathogenesis in genetically modified mice
B Mrkic1, J Pavlovic, T Rülicke
1Institut für Molekularbiologie Abt. I, Universität Zürich, Zürich, Switzerland.
Abstract:
Attenuated Edmonston measles virus (MV-Edm) is not pathogenic in standard mice. We show here that MV-Edm inoculated via the natural respiratory route has a limited propagation in the lungs of mice with a targeted mutation inactivating the alpha/beta interferon receptor. A high dose of MV-Edm administered intracerebrally is lethal for about half of these mice. To study the consequences of the availability of a high-affinity receptor for MV propagation, we generated alpha/beta interferon-defective mice expressing human CD46 with human-like tissue specificity. Intranasal infection of these mice with MV-Edm resulted in enhanced spread to the lungs and more prominent inflammatory response. Virus replication was also detected in peripheral blood mononuclear cells, the spleen, and the liver. Moreover, intracerebral inoculation of adult animals with low MV-Edm doses caused encephalitis with almost inevitably lethal outcome. We conclude that in mice alpha/beta interferon controls MV infection and that a high-affinity receptor facilitates, but is not strictly required for, MV spread and pathogenesis.
Insights
Alpha/beta interferon in mice controls measles virus (MV-Edm) infection. A high-affinity receptor aids MV spread and pathogenesis, but is not essential.
Area of Science:
- Virology
- Immunology
- Genetics
Background:
- Attenuated Edmonston measles virus (MV-Edm) typically shows limited pathogenicity in standard mice.
- Understanding measles virus (MV) pathogenesis requires models that mimic human susceptibility.
- Interferon signaling and receptor interactions are critical in viral control.
Purpose of the Study:
- To investigate the role of alpha/beta interferon in controlling MV infection in mice.
- To examine the impact of a high-affinity receptor (human CD46) on MV spread and pathogenesis.
- To establish a mouse model for studying MV encephalitis.
Main Methods:
- Infection of mice with targeted mutations in the alpha/beta interferon receptor.
- Generation of genetically modified mice expressing human CD46 with human-like tissue specificity.
- Intranasal and intracerebral inoculation of MV-Edm in different mouse models.
- Assessment of virus propagation, inflammatory responses, and clinical outcomes.
Main Results:
- MV-Edm showed limited lung propagation in mice lacking alpha/beta interferon receptors.
- Intracerebral MV-Edm inoculation was lethal in approximately half of these mice.
- Mice expressing human CD46 and lacking alpha/beta interferon exhibited enhanced MV spread to lungs, PBMCs, spleen, and liver.
- Intracerebral MV-Edm infection in these modified mice led to encephalitis with a high mortality rate.
Conclusions:
- Alpha/beta interferon signaling is a key determinant of MV infection control in mice.
- A high-affinity receptor facilitates MV spread and pathogenesis but is not strictly required.
- The developed mouse model is valuable for studying MV encephalitis and viral pathogenesis.