Respiratory syncytial virus infection of human respiratory epithelial cells enhances inducible nitric oxide synthase gene expression

Tsutsumi, Hiroyuki; Takeuchi, Ryoh; Ohsaki, Masaya; Seki, Kimihira; Chiba, Shunzo

doi:10.1002/jlb.66.1.99

Cited by 62 publications

(52 citation statements)

References 39 publications

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“…55 Indeed, we have previously demonstrated in vitro that the production of NO from epithelial cells infected with RSV correlates inversely with viral titer, an effect that was reversed by the NOS inhibitor NG-methyl-L-arginine. 56 Recently, Stark et al 57 demonstrated that in vivo inhibition of NOS-2 during RSV infection resulted in increased RSV titers in the lungs.…”

Section: Discussionmentioning

confidence: 98%

Eosinophils contribute to innate antiviral immunity and promote clearance of respiratory syncytial virus

Phipps

Lam

Mahalingam

et al. 2007

Blood

270

257

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Eosinophils are recruited to the lungs in response to respiratory syncytial virus (RSV) infection; however, their role in promoting antiviral host defense remains unclear. Here, we demonstrate that eosinophils express TLRs that recognize viral nucleic acids, are activated and degranulate after singlestranded RNA (ssRNA) stimulation of the TLR-7-MyD88 pathway, and provide host defense against RSV that is MyD88 dependent. In contrast to wild-type mice, virus clearance from lung tissue was more rapid in hypereosinophilic (interleukin-5 transgenic) mice. Transfer of wild-type but not MyD88-deficient eosinophils to the lungs of RSV-infected wild-type mice accelerated virus clearance and inhibited the development of airways hyperreactivity. Similar responses were observed when infected recipient mice were MyD88 deficient. Eosinophils isolated from infected hypereosinophilic MyD88-sufficient but not MyD88-deficient mice expressed greater amounts of IFN regulatory factor (IRF) - IntroductionThere are numerous studies addressing the contribution of eosinophilic leukocytes to immune mechanisms regulating allergic diseases and granulomatous and fibrotic disorders, and eosinophil recruitment in response to helminthic parasite infection has been well documented. 1 In contrast, there is only limited information on the role of eosinophils in immunity against infectious pathogens. Eosinophil recruitment was observed in response to acute severe respiratory syncytial virus (RSV) infection in human infants, 2-4 and infection of airway epithelial cells results in the expression of several eosinophil chemoattractants. 5,6 However, it is not at all clear whether eosinophils contribute to host defense or to the immunopathology observed in response to RSV infection. RSV infection is the most commonly identified cause of lower respiratory tract infections in infants, and severe disease has been associated with progression to childhood asthma, a disease state characterized by a mild to moderate eosinophilia. 7,8 In addition, exacerbations of established asthma are most frequently caused by viral infections, of which RSV has been implicated. 9 Recently, transcripts encoding Toll-like receptor (TLR)-1, TLR-4, TLR-7, TLR-9, and TLR-10, all of which coordinate innate and acquired immune responses, were shown to be expressed constitutively by eosinophils. 10 Recognition of viral nucleic acids, including double-stranded RNA (dsRNA), single-stranded RNA (ssRNA), and dsDNA, occurs via activation of TLR-3, TLR-7, and TLR-9, respectively, and results in the production of type I IFNs and the initiation of the antiviral host response. 11-15 RSV is a negative ssRNA virus that generates dsRNA during its replication cycle. Although TLR-3 and TLR-7 both recognize viral RNA, TLR-3 uses toll-interleukin receptor domain-containing adaptorinducing IFN-␤ (TRIF) and does not require MyD88, while TLR-7 signaling is MyD88 dependent. 12 These differences in adaptor usage, along with the activation of different IFN regulatory factors (IRFs), are proposed to provi...

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Section: Discussionmentioning

confidence: 98%

Eosinophils contribute to innate antiviral immunity and promote clearance of respiratory syncytial virus

Phipps

Lam

Mahalingam

et al. 2007

Blood

270

257

View full text Add to dashboard Cite

show abstract

“…This possibility exists because HBD2 induction at 8 -16 h post-infection (Fig. 1, B and C) coincides with NF-B activation (at 6 -16 h postinfection) (7,45) and TNF expression/production (7-10 h postinfection) (47,48) in RSV-infected cells. To examine the role of TNF in HBD2 induction, A549 cells were infected with RSV (0.2 m.o.i.)…”

Section: Rsv-and Tnf-mediated Expression Of Cell-associated and Secrementioning

confidence: 89%

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

Kota

Sabbah

Chang

et al. 2008

Journal of Biological Chemistry

140

137

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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...

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“…hRSV infection of epithelial cells in vitro induces the production of other chemokines, including RANTES, monocyte chemotactic protein 1 (MCP-1), and MIP-1␣, the last chemokine being of particular note because it is directly related to the inflammatory responses to both hRSV and PVM observed in vivo (90,136,169). Other prominent biochemical responses to hRSV infection in vitro include the production of inducible nitric oxide synthase and nitric oxide (155,201,356) beta interferon, IL-1␣, IL-6, and IL-11 and increased expression of cell surface markers intercellular cell adhesion molecule 1 (ICAM-1; CD54), CD18, vascular cell adhesion molecule (VCAM), major histocompatibility complex classes I and II, CD14, and CD15 (reviewed in reference 92). See also the section on gene microarray approaches in "Gene microarray expression studies" below.…”

Section: Cellular and Biochemical Responses (I) Syncytium Formationmentioning

confidence: 99%

Animal Pneumoviruses: Molecular Genetics and Pathogenesis

2004

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Pneumoviruses are single-stranded, negative-sense, nonsegmented RNA viruses of the family Paramyxoviridae, subfamily Pneumovirinae, and include pathogens that infect humans (respiratory syncytial virus and human metapneumovirus), domestic mammals (bovine, ovine, and caprine respiratory syncytial viruses), rodents (pneumonia virus of mice), and birds (avian metapneumovirus). Among the topics considered in this review are recent studies focused on the roles of the individual virus-encoded components in promoting virus replication as well as in altering and evading innate antiviral host defenses. Advances in the molecular technology of pneumoviruses and the emergence of recombinant pneumoviruses that are leading to improved virus-based vaccine formulations are also discussed. Since pneumovirus infection in natural hosts is associated with a profound inflammatory response that persists despite adequate antiviral therapy, we also review the recent experimental treatment strategies that have focused on combined antiviral, anti-inflammatory, and immunomodulatory approaches

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Respiratory syncytial virus infection of human respiratory epithelial cells enhances inducible nitric oxide synthase gene expression

Cited by 62 publications

References 39 publications

Eosinophils contribute to innate antiviral immunity and promote clearance of respiratory syncytial virus

Eosinophils contribute to innate antiviral immunity and promote clearance of respiratory syncytial virus

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

Animal Pneumoviruses: Molecular Genetics and Pathogenesis

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