Despite an effective vaccine, measles virus (MV) is still the seventh leading cause of death worldwide. MV causes significant morbidity an 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-acquired 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 an 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 target lymphocytes to downregulate cytokine production. The long range goal of this project, is to determine how wild-type MV interacts with the MV receptor CD46 to result in host-cell attachment, entry and modulation on 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 domain of the CD46 receptor that are responsible for interacting with wild-type MV to achieve virus binding, entry an 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 virus entry and immune function. Determining how the interaction between MV and CD46 influences intracellular signals is important not only for understanding how measles-induced immunosuppression occurs, but provides a potential tool for studying how virus-receptor interactions can modulate host cell functions.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI046441-01A1
Application #
6200588
Study Section
Virology Study Section (VR)
Program Officer
Meegan, James M
Project Start
2000-08-01
Project End
2005-07-31
Budget Start
2000-08-01
Budget End
2001-07-31
Support Year
1
Fiscal Year
2000
Total Cost
$310,625
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Hahm, Bumsuk; Arbour, Nathalie; Naniche, Denise et al. (2003) Measles virus infects and suppresses proliferation of T lymphocytes from transgenic mice bearing human signaling lymphocytic activation molecule. J Virol 77:3505-15
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