Despite an effective vaccine, measles virus (MV) is still the seventh leading cause of death worldwide. MV causes significant morbidity and mortality due to virus-associated immunosuppression and kills over 1 million children per year. Why is measles still a public health problem when a vaccine is available? The extremely infectious nature of the virus, interference with MV vaccination by maternally-inherited antibodies and waning immunity in vaccines all contribute to the stubborn resistance of MV to eradication. The interaction between viruses and cell-surface receptors is a major determinant of virus tropism and pathogenesis. For MV, the cell-surface receptor has been identified as the complement receptor CD46. The normal function of CD46 is to bind complement components on the cell surface and prevent their deposition on host cells. Previous studies have shown that complement C3b, the primary ligand for CD46, interacts with regions of the extracellular domain of CD46 near the membrane. Laboratory strains of MV, in contrast, interact with the N-terminal third of the extracellular domain of CD46. This interaction not only results in MV attachment and entry, but can also signal host lymphocytes to downregulate cytokine production. The long range goal of this project is to determine how wild-type measles virus (MV) interacts with the MV receptor CD46 to result in host-cell attachment, entry and modulation of intracellular signaling. First, emphasis is placed on mapping the specific interaction between wild-type strains of MV and the extracellular domain of the CD46 receptor. A combined molecular genetic and structural analysis will be used to identify and characterize the domains of the CD46 receptor that are responsible for interacting with wild-type MVs to achieve virus binding, entry and immunosuppressive effects in target host cells. A second emphasis of this grant is to characterize the signaling events that occur upon liganding of CD46 by wild-type and laboratory strains of MV and how these events regulate viral entry and immune function. Determining how the interaction between MV and CD46 influences intracellular signals is not only important for understanding how measles-induced immunosuppression occurs, but provides a potential tool for studying how virus-receptor interactions can modulate host cell function.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
5R29AI041514-03
Application #
6163923
Study Section
Experimental Virology Study Section (EVR)
Program Officer
Meegan, James M
Project Start
1998-03-01
Project End
2000-09-14
Budget Start
2000-03-01
Budget End
2000-09-14
Support Year
3
Fiscal Year
2000
Total Cost
$85,677
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Manchester, Marianne; Smith, Kent A; Eto, Danelle S et al. (2002) Targeting and hematopoietic suppression of human CD34+ cells by measles virus. J Virol 76:6636-42
Patterson, J B; Manchester, M; Oldstone, M B (2001) Disease model: dissecting the pathogenesis of the measles virus. Trends Mol Med 7:85-8
Manchester, M; Rall, G F (2001) Model Systems: transgenic mouse models for measles pathogenesis. Trends Microbiol 9:19-23
Manchester, M; Naniche, D; Stehle, T (2000) CD46 as a measles receptor: form follows function. Virology 274:10-May
Naniche, D; Yeh, A; Eto, D et al. (2000) Evasion of host defenses by measles virus: wild-type measles virus infection interferes with induction of Alpha/Beta interferon production. J Virol 74:7478-84
Manchester, M; Eto, D S; Valsamakis, A et al. (2000) Clinical isolates of measles virus use CD46 as a cellular receptor. J Virol 74:3967-74
Manchester, M; Eto, D S; Oldstone, M B (1999) Characterization of the inflammatory response during acute measles encephalitis in NSE-CD46 transgenic mice. J Neuroimmunol 96:207-17