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 i s 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 i s 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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA090636-04
Application #
6935304
Study Section
Experimental Virology Study Section (EVR)
Program Officer
Fu, Yali
Project Start
2002-09-01
Project End
2007-04-30
Budget Start
2005-09-01
Budget End
2007-04-30
Support Year
4
Fiscal Year
2005
Total Cost
$257,210
Indirect Cost
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905
Navaratnarajah, Chanakha K; Kumar, Swati; Generous, Alex et al. (2014) The measles virus hemagglutinin stalk: structures and functions of the central fusion activation and membrane-proximal segments. J Virol 88:6158-67
Mateo, Mathieu; Navaratnarajah, Chanakha K; Cattaneo, Roberto (2014) Structural basis of efficient contagion: measles variations on a theme by parainfluenza viruses. Curr Opin Virol 5:16-23
Apte-Sengupta, Swapna; Navaratnarajah, Chanakha K; Cattaneo, Roberto (2013) Hydrophobic and charged residues in the central segment of the measles virus hemagglutinin stalk mediate transmission of the fusion-triggering signal. J Virol 87:10401-4
Navaratnarajah, Chanakha K; Negi, Surendra; Braun, Werner et al. (2012) Membrane fusion triggering: three modules with different structure and function in the upper half of the measles virus attachment protein stalk. J Biol Chem 287:38543-51
Apte-Sengupta, Swapna; Negi, Surendra; Leonard, Vincent H J et al. (2012) Base of the measles virus fusion trimer head receives the signal that triggers membrane fusion. J Biol Chem 287:33026-35
Navaratnarajah, Chanakha K; Miest, Tanner S; Carfi, Andrea et al. (2012) Targeted entry of enveloped viruses: measles and herpes simplex virus I. Curr Opin Virol 2:43-9
Mühlebach, Michael D; Mateo, Mathieu; Sinn, Patrick L et al. (2011) Adherens junction protein nectin-4 is the epithelial receptor for measles virus. Nature 480:530-3
Navaratnarajah, Chanakha K; Oezguen, Numan; Rupp, Levi et al. (2011) The heads of the measles virus attachment protein move to transmit the fusion-triggering signal. Nat Struct Mol Biol 18:128-34
Ferreira, Claudia S Antunes; Frenzke, Marie; Leonard, Vincent H J et al. (2010) Measles virus infection of alveolar macrophages and dendritic cells precedes spread to lymphatic organs in transgenic mice expressing human signaling lymphocytic activation molecule (SLAM, CD150). J Virol 84:3033-42
Funke, Sabrina; Maisner, Andrea; Muhlebach, Michael D et al. (2008) Targeted cell entry of lentiviral vectors. Mol Ther 16:1427-36

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