Related Experiment Videos
Lymphatic dissemination and comparative pathology of recombinant measles viruses in genetically modified mice
B Mrkic1, B Odermatt, M A Klein
1Molecular Biology Institute, University of Zurich, Switzerland.
Abstract:
The dissemination of the Edmonston measles virus (Ed-MV) vaccine strain was studied with genetically modified mice defective for the alpha/beta interferon receptor and expressing human CD46 with human-like tissue specificity and efficiency. A few days after intranasal infection, macrophages expressing Ed-MV RNA were detected in the lungs, in draining lymph nodes, and in the thymus. In lymph nodes, large syncytia which stained positive for viral RNA and for macrophage surface marker proteins were found and apoptotic cell death was monitored. In the thymus, smaller syncytia which stained positive for macrophage and dendritic cell markers were detected. Thus, macrophages appear to be the main vectors for dissemination of MV infection in these mice; human macrophages may have a similar function in the natural host. We then compared the pathogenicities of two recombinant viruses lacking the C or V nonstructural proteins to that of the parental strain, Ed-MV. These viruses were less effective in spreading through the lymphatic system and, unlike Ed-MV, were not detected in the liver. After intracerebral inoculation the recombinant viruses caused lethal disease less often than Ed-MV and induced distinctive patterns of gliosis and inflammation. Ed-MV was reisolated from brain tissue, but its derivatives were not. C- and V-defective viruses should be considered as more-attenuated MV vaccine candidates.
Insights
Macrophages are key in measles virus (Ed-MV) spread, acting as primary vectors in genetically modified mice. Viruses lacking C or V proteins show reduced pathogenicity, suggesting potential as safer measles vaccine candidates.
Area of Science:
- Virology
- Immunology
- Genetics
Background:
- Measles virus (MV) infection and dissemination pathways are not fully understood.
- Genetically modified mouse models are crucial for studying viral pathogenesis and vaccine development.
Purpose of the Study:
- To investigate the role of macrophages in measles virus (Edmonston-MV) dissemination using a novel mouse model.
- To compare the pathogenicity of Ed-MV with recombinant viruses lacking nonstructural C or V proteins.
Main Methods:
- Intranasal and intracerebral inoculation of genetically modified mice (interferon receptor deficient, expressing human CD46) with Ed-MV and recombinant viruses.
- Detection of viral RNA, syncytia formation, apoptotic cell death, and specific cell markers (macrophages, dendritic cells) in various tissues.
- Assessment of viral spread, disease lethality, and neuropathological changes (gliosis, inflammation).
Main Results:
- Macrophages expressing Ed-MV RNA were identified in lungs, lymph nodes, and thymus, forming syncytia and suggesting their role as dissemination vectors.
- Recombinant viruses lacking C or V proteins exhibited reduced lymphatic spread, were not detected in the liver, and caused less lethal disease after intracerebral inoculation.
- Distinct patterns of gliosis and inflammation were observed with recombinant viruses, which were not reisolated from brain tissue, unlike the parental Ed-MV.
Conclusions:
- Macrophages are likely the primary vectors for measles virus dissemination in this mouse model, potentially mirroring their role in human hosts.
- Measles viruses deficient in C and V nonstructural proteins demonstrate reduced pathogenicity and neuropathogenesis.
- These C- and V-defective viruses represent promising candidates for more attenuated measles virus vaccines.