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

Abstract

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-␣/␤-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-␣/␤. During our efforts to study this pathway, we identified HBD2 (human ␤-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 ␤-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.Nonsegmented negative strand RNA viruses (superfamily Mononegaviridae) constitute highly pathogenic human viruses that cause high morbidity. Human respiratory syncytial virus (RSV), 2 a nonsegmented negative strand virus, is an important human lung tropic respiratory tract pathogen causing high morbidity and mortality among infants, children, and elderly by manifesting disease states, including pneumonia, and bronchiolitis (1, 2). To date, no effective vaccine or antiviral therapy exists for RSV. Therefore, elucidation of innate immune antiviral response induced by RSV holds significant potential for development of effective antiviral therapies in the near future.The innate immune antiviral response against viruses represents an important host defense mechanism (3). Innate immunity includes the first line of defense by the host to combat virus infection before an orchestrated adaptive immune response involving immune cell priming, and antibody production is launched. Two key molecules regulating the innate antiviral function are interferon regulatory factors (IRFs) and NF-B (4). These two transcription factors are activated either individually or together in infected cells, resulting in the expression and production of interferon-␣/␤ (IFN), which are potent antiviral cytokines (5, 6). IFN produced from infected cells binds to their...

Characteristic changes in microbial community composition and expression of innate immune genes in acute appendicitis

“…12 As expected, the abundance of hBD-2 and hBD-3 was significantly induced in the inflamed appendices. Known inducers of these b-defensins, like IL-1b 14 and TNFa, 35 were found to be up-regulated in appendicitis and might be responsible for this regulation of hBD-2 and hBD-3. TLRs 1, 4 and 8 are also strongly induced in appendicitis, and these receptors are reported to be inducers, as well as targets of both b-defensins.…”

Both copy number and sequence variations affect expression of human DEFB4

“…As defensin expression is mediated by the NF-kB pathway, 35,36 we checked the analyzed region regarding NF-kB TFBSs. Five potential NF-kB TFBS were found at following positions: chr8…”

Human α-Defensins Inhibit BK Virus Infection by Aggregating Virions and Blocking Binding to Host Cells

“…␣-Defensins inhibits multiple enveloped viruses including herpes simplex virus, influenza virus, cytomegalovirus, rhabdovirus, and HIV-1 (23)(24)(25)(26). ␤-Defensins exhibit antiviral activity against herpes simplex virus, respiratory syncytial virus, vaccinia virus, and HIV-1 (27)(28)(29)(30). Interestingly, infection and replication of some viruses can induce the expression and secretion of defensins in host cells (27,31).…”

“…␤-Defensins exhibit antiviral activity against herpes simplex virus, respiratory syncytial virus, vaccinia virus, and HIV-1 (27)(28)(29)(30). Interestingly, infection and replication of some viruses can induce the expression and secretion of defensins in host cells (27,31). Recent studies have shown that ␣-defensins also inhibit non-enveloped viruses, such as adenovirus and papillomavirus, and have begun to unravel the mechanism of action (32)(33)(34).…”