Abstract

We have isolated and characterized a 100-120 kDa glycoprotein which serves as the receptor for mouse hepatitis virus, a murine coronavirus. Immunoaffinity purification of the receptor, cloning and expression of the receptor gene revealed that the receptor is a member of the immunoglobulin superfamily of glycoproteins, serologically related to proteins in the carcinoembryonic antigen family. A monoclonal antibody which binds to the receptor on mouse cells blocks MHV infection in vitro and partially protects mice from infection in vivo. We will characterize the domains of the receptor glycoprotein and the viral attachment glycoprotein which interact using recombinant DNA technology and protein chemistry as well as ultrastructural and X-ray crystallography. The information obtained will be used to develop drugs which interfere with the virus-receptor interaction, and these will be tested for protection from MHV infection in vitro and in a mouse model system. Analogous studies will be done to characterize the receptor for human coronavirus HCV229E which causes colds. Development of anti-receptor drugs may provide a useful approach to the prevention and treatment of coronavirus infections of man and animals.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01AI026075-07
Application #
3547091
Study Section
Special Emphasis Panel (SRC (50))
Project Start
1988-04-01
Project End
1995-03-31
Budget Start
1993-04-01
Budget End
1994-03-31
Support Year
7
Fiscal Year
1993
Total Cost
Indirect Cost

  Institution

Name
Henry M. Jackson Fdn for the Adv Mil/Med
Department
Type
DUNS #
City
Rockville
State
MD
Country
United States
Zip Code
20817

  Publications

Tusell, Sonia M; Schittone, Stephanie A; Holmes, Kathryn V (2007) Mutational analysis of aminopeptidase N, a receptor for several group 1 coronaviruses, identifies key determinants of viral host range. J Virol 81:1261-73
Wentworth, David E; Tresnan, D B; Turner, B C et al. (2005) Cells of human aminopeptidase N (CD13) transgenic mice are infected by human coronavirus-229E in vitro, but not in vivo. Virology 335:185-97
Breslin, Jamie J; Mork, Irene; Smith, M K et al. (2003) Human coronavirus 229E: receptor binding domain and neutralization by soluble receptor at 37 degrees C. J Virol 77:4435-8
Tan, Kemin; Zelus, Bruce D; Meijers, Rob et al. (2002) Crystal structure of murine sCEACAM1a[1,4]: a coronavirus receptor in the CEA family. EMBO J 21:2076-86
Blau, D M; Holmes, K V (2001) Human coronavirus HCoV-229E enters susceptible cells via the endocytic pathway. Adv Exp Med Biol 494:193-8
Wentworth, D E; Holmes, K V (2001) Molecular determinants of species specificity in the coronavirus receptor aminopeptidase N (CD13): influence of N-linked glycosylation. J Virol 75:9741-52
Wentworth, D E; Holmes, K V (2001) Addition of a single glycosylation site to hAPN blocks human coronavirus-229E receptor activity. Adv Exp Med Biol 494:199-204
Robitaille, J; Izzi, L; Daniels, E et al. (1999) Comparison of expression patterns and cell adhesion properties of the mouse biliary glycoproteins Bbgp1 and Bbgp2. Eur J Biochem 264:534-44
Tresnan, D B; Holmes, K V (1998) Feline aminopeptidase N is a receptor for all group I coronaviruses. Adv Exp Med Biol 440:69-75
Wessner, D R; Shick, P C; Lu, J H et al. (1998) Mutational analysis of the virus and monoclonal antibody binding sites in MHVR, the cellular receptor of the murine coronavirus mouse hepatitis virus strain A59. J Virol 72:1941-8

Showing the most recent 10 out of 22 publications