title: Nerve growth factor modulates human rhinovirus infection in airway epithelial cells by controlling ICAM-1 expression.
abstract: Human rhinoviruses (HRV) are the most common agent of upper respiratory infections and an important cause of lower respiratory tract symptoms. Our previous research with other viral pathogens has shown that virus-induced airway inflammation and hyperreactivity involve neurotrophic pathways that also affect tropism and severity of the infection. The goals of this study were to analyze systematically the expression of key neurotrophic factors and receptors during HRV-16 infection of human airway epithelial cells and to test the hypothesis that neurotrophins modulate HRV infection by controlling the expression of a major cellular receptor for this virus, the intercellular adhesion molecule 1 (ICAM-1). Neurotrophins and ICAM-1 expression were analyzed at the mRNA level by real-time PCR and at the protein level by flow cytometry and immunocytochemistry. A small inhibitory RNA (siRNA) or a specific blocking antibody was utilized to suppress nerve growth factor (NGF) expression and measure its effects on viral replication and virus-induced cell death. Nasal and bronchial epithelial cells were most susceptible to HRV-16 infection at 33°C and 37°C, respectively, and a significant positive relationship was noted between expression of NGF and tropomyosin-related kinase A (TrkA) and virus copy number. ICAM-1 expression was dose dependently upregulated by exogenous NGF and significantly downregulated by NGF inhibition with corresponding decrease in HRV-16 replication. NGF inhibition also increased apoptotic death of infected cells. Our results suggest that HRV upregulates the NGF-TrkA pathway in airway epithelial cells, which in turn amplifies viral replication by increasing HRV entry via ICAM-1 receptors and by limiting apoptosis.
authors.affiliation: Department of Pediatrics and Pediatric Research Institute, West Virginia University School of Medicine, 1 Medical Center Dr., Morgantown, WV 26506-9214, USA.
authors.forename: Sreekumar
authors.initials: S
authors.lastname: Othumpangat
authors.forename: Michael
authors.initials: M
authors.lastname: Regier
authors.forename: Giovanni
authors.initials: G
authors.lastname: Piedimonte
mesh_terms: D057134:Antibodies, Neutralizing / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001980:Bronchi / Q000378:metabolism / Q000473:pathology / Q000821:virology; D002460:Cell Line; D004847:Epithelial Cells / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D005786:Gene Expression Regulation; D054884:Host-Pathogen Interactions; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism*; D020932:Nerve Growth Factor / Q000378:metabolism* / Q000494:pharmacology; D010850:Picornaviridae Infections / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D020545:Respiratory Mucosa / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D012229:Rhinovirus / Q000502:physiology*; D015398:Signal Transduction; D019562:Viral Load / Q000187:drug effects; D014779:Virus Replication / Q000187:drug effects
chemical_list: D057134:Antibodies, Neutralizing; D018799:Intercellular Adhesion Molecule-1; D020932:Nerve Growth Factor