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J. Biol. Chem., Vol. 283, Issue 33, 22417-22429, August 15, 2008

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Role of Human β-Defensin-2 during Tumor Necrosis Factor-/NF-B-mediated Innate Antiviral Response against Human Respiratory Syncytial Virus^*

From the Department of Microbiology and Immunology, The University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229

Human respiratory syncytial virus (RSV) constitutes a highly pathogenic virus that infects lung epithelial cells to cause a wide spectrum of respiratory diseases. Our recent studies have revealed the existence of an interferon-/β-independent, innate antiviral response against RSV that was dependent on activation of NF-B. We demonstrated that NF-B inducing pro-inflammatory cytokines like tumor necrosis factor- (TNF) confers potent antiviral function against RSV in an NF-B-dependent fashion, independent of interferon-/β. During our efforts to study this pathway, we identified HBD2 (human β-defensin-2), a soluble secreted cationic protein as an antiviral factor induced during NF-B-dependent innate antiviral activity in human lung epithelial cells. Our results demonstrated that HBD2 is induced by TNF and RSV in an NF-B-dependent manner. Induction of HBD2 in infected cells was mediated by the paracrine/autocrine action of TNF produced upon RSV infection. HBD2 plays a critical role during host defense, because purified HBD2 drastically inhibited RSV infection. We also show that the antiviral mechanism of HBD2 involves blocking of viral cellular entry possibly because of destabilization/disintegration of the viral envelope. The important role of HBD2 in the innate response was also evident from loss of antiviral activity of TNF upon HBD2 silencing by short interfering RNA. The in vivo physiological relevance of HBD2 in host defense was apparent from induction of murine β-defensin-4 (murine counterpart of HBD2) in lung tissues of RSV-infected mice. Thus, HBD2 functions as an antiviral molecule during NF-B-dependent innate antiviral immunity mediated by the autocrine/paracrine action of TNF.

Received for publication, December 21, 2007 , and in revised form, June 10, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grants AI069062 and CA129246 (to S. B.) and T32-DE14318 (to S. B. and A. S.). This work was also supported by American Lung Association National Biomedical Research Grant RG-49629-N (to S. B.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement"in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1–S6.

¹ To whom correspondence should be addressed: Dept. of Microbiology and Immunology, University of Texas Health Science Center, San Antonio, 7703 Floyd Curl Dr., MC-7758, San Antonio, TX 78229. Fax: 210-567-6612; E-mail: bose{at}uthscsa.edu.

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