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Journal of Virology, July 2002, p. 6800-6814, Vol. 76, No. 13
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.13.6800-6814.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Identification of NF-{kappa}B-Dependent Gene Networks in Respiratory Syncytial Virus-Infected Cells

Bing Tian,1 Yuhong Zhang,1 Bruce A. Luxon,2,3 Roberto P. Garofalo,4,5 Antonella Casola,4 Mala Sinha,2,3 and Allan R. Brasier1,6*

Departments of Medicine,1 Human Biological Chemistry and Genetics,3 Pediatrics,4 Microbiology and Immunology,5 Sealy Center for Structural Biology,2 Sealy Center for Molecular Sciences, The University of Texas Medical Branch, Galveston, Texas 77555-10606

Received 5 November 2001/ Accepted 28 March 2002

Respiratory syncytial virus (RSV) is a mucosa-restricted virus that is a leading cause of epidemic respiratory tract infections in children. In epithelial cells, RSV replication activates nuclear translocation of the inducible transcription factor nuclear factor {kappa}B (NF-{kappa}B) through proteolysis of its cytoplasmic inhibitor, I{kappa}B. In spite of a putative role in mediating virus-inducible gene expression, the spectrum of NF-{kappa}B-dependent genes induced by RSV infection has not yet been determined. To address this, we developed a tightly regulated cell system expressing a nondegradable, epitope-tagged I{kappa}B{alpha} isoform (Flag-I{kappa}B{alpha} Mut) whose expression could be controlled by exogenous addition of nontoxic concentrations of doxycycline. Flag-I{kappa}B{alpha} Mut expression potently inhibited I{kappa}B{alpha} proteolysis, NF-{kappa}B binding, and NF-{kappa}B-dependent gene transcription in cells stimulated with the prototypical NF-{kappa}B-activating cytokine tumor necrosis factor alpha (TNF-{alpha}) and in response to RSV infection. High-density oligonucleotide microarrays were then used to profile constitutive and RSV-induced gene expression in the absence or presence of Flag-I{kappa}B{alpha} Mut. Comparison of these profiles revealed 380 genes whose expression was significantly changed by the dominant-negative NF-{kappa}B. Of these, 236 genes were constitutive (not RSV regulated), and surprisingly, only 144 genes were RSV regulated, representing numerically ~10% of the total population of RSV-inducible genes at this time point. Hierarchical clustering of the 144 RSV- and Flag-I{kappa}B{alpha} Mut-regulated genes identified two discrete gene clusters. The first group had high constitutive expression, and its expression levels fell in response to RSV infection. In this group, constitutive mRNA expression was increased by Flag-I{kappa}B{alpha} Mut expression, and the RSV-induced decrease in expression was partly inhibited. In the second group, constitutive expression was very low (or undetectable) and, after RSV infection, expression levels strongly increased. In this group, NF-{kappa}B was required for RSV-inducible expression because Flag-I{kappa}B{alpha} Mut expression blocked their induction by RSV. This latter cluster includes chemokines, transcriptional regulators, intracellular proteins regulating translation and proteolysis, and secreted proteins (complement components and growth factor regulators). These data suggest that NF-{kappa}B action induces global cellular responses after viral infection.

* Corresponding author. Mailing address: Division of Endocrinology, MRB 8.138, The University of Texas Medical Branch, 301 University Blvd., Galveston, TX 77555-1060. Phone: (409) 772-2824. Fax: (409) 772-8709. E-mail: arbrasie{at}utmb.edu.

Journal of Virology, July 2002, p. 6800-6814, Vol. 76, No. 13
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.13.6800-6814.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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