DESCRIPTION (provided by applicant): Measles, caused by wild-type measles viruses (MV), is one of the leading causes of infant death in developing countries. The immune suppression that accompanies measles significantly enhances an individual's susceptibility to secondary infections and these account for most of the morbidity and mortality associated with the disease. Vaccination with the live attenuated strain Edmonston (MV-Edm) prevents measles-related fatalities and only rarely results in the development of mild symptoms. Cell entry may have a central role in MV pathology: it appears that most wild-type MV strains preferentially use the immune cell specific protein SLAM as a receptor, whereas MV-Edm enters cells more efficiently using the ubiquitous protein CD46. Moreover three different morbilliviruses (MV, canine distemper virus, and rinderpest virus) all enter cells through SLAM (human, canine or bovine) and are immunosupressive. We will test the hypothesis that the relative efficiency of cell entry through SLAM and CD46 is a major determinant of viral dissemination in immune cells and of the pathogenic outcome of infections. Our first aim is to characterize the mechanism of attachment of wild-type and attenuated MV through SLAM and CD46. This will be accomplished by measuring the binding of soluble and membrane-associated forms of SLAM and CD46 to soluble variants of the H protein and to virus particles. We will define the surface areas of the H protein which interact with SLAM and CD46, and produce recombinant viruses with reduced binding to one, the other, or both receptors. Our second aim is to assess the consequences of specific cell entry for dissemination in immune cells. Towards this, we have shown that recombinant MVs that express green fluorescent protein are ideally suited to follow infection of human peripheral blood mononuclear cells (PBMC). We will extend these studies to novel MV variants with tight receptor specificity. Moreover, to produce a small animal model that recapitulates the pathology of wild type MV strains we will obtain mice that express SLAM with human-like tissue specificity, and breed them with the mice we produced expressing human CD46 with human-like tissue specificity. We will infect these mice with recombinant viruses that differ only in their attachment protein, or that maintain a constant H protein but have a different genomic backbone, and follow viral spread in PBMC, lymphatic organs, and systemically.
|Effective start/end date||4/1/01 → 2/28/13|