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Adaptation of wild-type measles virus to CD46 receptor usage
L Nielsen1, M Blixenkrone-Møller, M Thylstrup
1Department of Medical Microbiology and Immunology, Panum Institute, University of Copenhagen, Copenhagen, Denmark.
Abstract:
Vaccine strains of measles virus (MV) use CD46 as receptor and downregulate CD46 from the surface of infected cells. MVs isolated and passaged on B-lymphoid cells (wild-type MVs) seem to use another receptor and do not downregulate CD46. In the present study, we found that isolation of MV on human or marmoset B-lymphoid cells did not alter the MV haemagglutinin (H) protein relative to that in the patient. The wild-type isolates were adapted to the human epithelial HEp-2 cell line or the monkey fibroblast Vero cell line. All HEp-2 cell adapted viruses and 1 out of 4 Vero cell adapted viruses acquired the capacity to use CD46 as receptor, as measured by their ability to infect murine cells expressing human CD46. Adaptation to CD46 receptor usage was coupled to substitution of amino acid 481 of the MV H protein from asparagine to tyrosine but not to CD46 downregulation. The present study demonstrates that CD46 receptor usage can be induced by adaptation of wild-type MV to cells that do not express a wild-type receptor and suggests that a similar mechanism acted on the progenitor viruses of the present MV vaccine strains during their isolation and attenuation.
Insights
Measles virus (MV) vaccine strains use CD46, unlike wild-type MVs. Adapting wild-type MV to new cell lines induced CD46 receptor usage, mimicking vaccine strain origins.
Area of Science:
- Virology
- Immunology
- Cell Biology
Background:
- Measles virus (MV) vaccine strains utilize CD46 as a receptor and downregulate it on infected cells.
- Wild-type MVs, isolated on B-lymphoid cells, appear to use a different receptor and do not downregulate CD46.
Purpose of the Study:
- To investigate the adaptation of wild-type measles virus (MV) to new cell lines and its effect on receptor usage.
- To understand the mechanism by which MV gains the ability to use CD46 as a receptor.
Main Methods:
- Isolation and passaging of wild-type MV on B-lymphoid cells.
- Adaptation of MV isolates to human epithelial HEp-2 and monkey fibroblast Vero cell lines.
- Assessment of CD46 receptor usage by measuring the infectivity of adapted viruses on murine cells expressing human CD46.
Main Results:
- Adaptation to HEp-2 cells and partially to Vero cells conferred CD46 receptor usage capacity to wild-type MV.
- Acquisition of CD46 receptor usage was associated with a specific amino acid substitution (N481Y) in the MV hemagglutinin (H) protein.
- CD46 receptor usage induction did not result in CD46 downregulation.
Conclusions:
- Wild-type MV can acquire CD46 receptor usage through adaptation to cell lines lacking its natural receptor.
- This adaptation mechanism, involving specific H protein mutations, likely mirrors the process during the isolation and attenuation of current MV vaccine strains.