Role of human beta-defensin-2 during tumor necrosis factor-alpha/NF-kappaB-mediated innate antiviral response against human respiratory syncytial virus.
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-alpha/beta-independent, innate antiviral response against RSV that was dependent on activation of NF-kappaB. We demonstrated that NF-kappaB inducing pro-inflammatory cytokines like tumor necrosis factor-alpha (TNF) confers potent antiviral function against RSV in an NF-kappaB-dependent fashion, independent of interferon-alpha/beta. During our efforts to study this pathway, we identified HBD2 (human beta-defensin-2), a soluble secreted cationic protein as an antiviral factor induced during NF-kappaB-dependent innate antiviral activity in human lung epithelial cells. Our results demonstrated that HBD2 is induced by TNF and RSV in an NF-kappaB-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 beta-defensin-4 (murine counterpart of HBD2) in lung tissues of RSV-infected mice. Thus, HBD2 functions as an antiviral molecule during NF-kappaB-dependent innate antiviral immunity mediated by the autocrine/paracrine action of TNF.
Kota
Srikanth
S
Department of Microbiology and Immunology, The University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229, USA.
Sabbah
Ahmed
A
Chang
Te Hung
TH
Harnack
Rosalinda
R
Xiang
Yan
Y
Meng
Xiangzhi
X
Bose
Santanu
S
D000256:Adenoviridae / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D000818:Animals; D019921:Biotinylation; D002460:Cell Line; D017931:DNA Primers; D017930:Genes, Reporter; D006801:Humans; D008168:Lung; D008715:Methionine / Q000378:metabolism; D016328:NF-kappa B / Q000502:physiology*; D012367:RNA, Viral / Q000235:genetics / Q000302:isolation & purification; D012136:Respiratory Syncytial Viruses / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013462:Sulfur Radioisotopes; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*; D023083:beta-Defensins / Q000187:drug effects / Q000502:physiology*
C106641:DEFB4A protein, human; D017931:DNA Primers; D016328:NF-kappa B; D012367:RNA, Viral; D013462:Sulfur Radioisotopes; D014409:Tumor Necrosis Factor-alpha; D023083:beta-Defensins; D008715:Methionine