About half of all common colds, one of the most frequent infections of humans, are caused by the human rhinoviruses. These viruses are members of the Picornaviridae, a family composed of small, non-enveloped positive strand RNA viruses. The pathogenesis of rhinovirus infection is poorly understood because the viruses replicate only in higher primates. A mouse model for rhinovirus infection would provide information about rhinovirus pathogenesis and stimulate the identification of antiviral and anti-inflammatory drugs. We propose to isolate rhinovirus variants that can replicate in mouse cells, identify mutations responsible for the change in host range, and study the mechanism of action of these mutations. Mouse-adapted rhinoviruses will be used to infect transgenic mice expressing human ICAM-1, the cellular receptor for major group human rhinoviruses.
Two specific aims are proposed.
Aim 1 : Determine the molecular basis of rhinovirus host range. Rhinovirus type 16 has been found to replicate in mouse cells expressing the viral receptor, human ICAM-1, and a viral variant was selected that replicates more efficiently in these cells and causes extensive cell death. The mutations that confer this host range phenotype are located in viral nonstructural polypeptides 2B and 2C. Experiments are designed to determine how these mutations influence viral replication, by determining their effect on viral RNA and protein synthesis, and their effects on the host cell membranes. Host cell proteins that interact with 2B and 2C will be identified to determine the mechanism of action of the host range mutations.
Aim 2 : Develop a transgenic mouse model for rhinovirus infection. Transgenic mice that express human ICAM-1 in the respiratory tract will be developed. Human ICAM-1 transgenic mice will be infected with rhinovirus type 16 and rhinovirus type 16 adapted to mouse cells expressing human ICAM-1 to study the pathogenesis of rhinovirus infection, including the sites of virus replication within the respiratory tract, the extent of cell damage in the host, the nature of the immune response, and the role of the immune response in pathogenesis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI050754-01
Application #
6420865
Study Section
Virology Study Section (VR)
Program Officer
Lambert, Linda C
Project Start
2002-02-01
Project End
2007-01-31
Budget Start
2002-02-01
Budget End
2003-01-31
Support Year
1
Fiscal Year
2002
Total Cost
$278,967
Indirect Cost
Name
Columbia University (N.Y.)
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
167204994
City
New York
State
NY
Country
United States
Zip Code
10032
Rasmussen, Angela L; Racaniello, Vincent R (2011) Selection of rhinovirus 1A variants adapted for growth in mouse lung epithelial cells. Virology 420:82-8
Racaniello, Vincent R (2010) Social media and microbiology education. PLoS Pathog 6:e1001095
Drahos, Jennifer; Racaniello, Vincent R (2009) Cleavage of IPS-1 in cells infected with human rhinovirus. J Virol 83:11581-7
Barral, Paola M; Sarkar, Devanand; Fisher, Paul B et al. (2009) RIG-I is cleaved during picornavirus infection. Virology 391:171-6
Morrison, Juliet M; Racaniello, Vincent R (2009) Proteinase 2Apro is essential for enterovirus replication in type I interferon-treated cells. J Virol 83:4412-22
Barral, Paola M; Sarkar, Devanand; Su, Zao-zhong et al. (2009) Functions of the cytoplasmic RNA sensors RIG-I and MDA-5: key regulators of innate immunity. Pharmacol Ther 124:219-34
Barral, Paola M; Morrison, Juliet M; Drahos, Jennifer et al. (2007) MDA-5 is cleaved in poliovirus-infected cells. J Virol 81:3677-84
Kauder, Steven; Kan, Sherry; Racaniello, Vincent R (2006) Age-dependent poliovirus replication in the mouse central nervous system is determined by internal ribosome entry site-mediated translation. J Virol 80:2589-95
Harris, Julie R; Racaniello, Vincent R (2005) Amino acid changes in proteins 2B and 3A mediate rhinovirus type 39 growth in mouse cells. J Virol 79:5363-73
Harris, Julie R; Racaniello, Vincent R (2003) Changes in rhinovirus protein 2C allow efficient replication in mouse cells. J Virol 77:4773-80