Advances in understanding respiratory syncytial virus infection in airway epithelial cells and consequential effects on the immune response

Lay, Margarita K.; González, Pablo A.; León, Mónica; Céspedes, Pablo F.; Bueno, Susan M.; Riedel, Claudia A.; Kalergis, Alexis M.

doi:10.1016/j.micinf.2012.11.012

Cited by 54 publications

(66 citation statements)

References 83 publications

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“…RSV infection triggers a loss of ciliated cells and Goblet cell metaplasia associated with enhanced MUC5AC production [6–9]. Furthermore, RSV infection causes the release of numerous pro-inflammatory chemokines and cytokines from bronchial epithelial cells and entails an imbalance between an enhanced reactive oxygen species (ROS) production and a compromised antioxidant enzymatic armamentarium [10,11]. Collectively, given these numerous effects, bronchial epithelial cells are considered key players of RSV-induced lung diseases.…”

Section: Introductionmentioning

confidence: 99%

Roflumilast Inhibits Respiratory Syncytial Virus Infection in Human Differentiated Bronchial Epithelial Cells

et al. 2013

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Respiratory syncytial virus (RSV) causes acute exacerbations in COPD and asthma. RSV infects bronchial epithelial cells (HBE) that trigger RSV associated lung pathology. This study explores whether the phosphodiesterase 4 (PDE4) inhibitor Roflumilast N-oxide (RNO), alters RSV infection of well-differentiated HBE (WD-HBE) in vitro. WD-HBE were RSV infected in the presence or absence of RNO (0.1-100 nM). Viral infection (staining of F and G proteins, nucleoprotein RNA level), mRNA of ICAM-1, ciliated cell markers (digital high speed videomicroscopy, β-tubulin immunofluorescence, Foxj1 and Dnai2 mRNA), Goblet cells (PAS), mRNA of MUC5AC and CLCA1, mRNA and protein level of IL-13, IL-6, IL-8, TNFα, formation of H2O2 and the anti-oxidative armamentarium (mRNA of Nrf2, HO-1, GPx; total antioxidant capacity (TAC) were measured at day 10 or 15 post infection. RNO inhibited RSV infection of WD-HBE, prevented the loss of ciliated cells and markers, reduced the increase of MUC5AC and CLCA1 and inhibited the increase of IL-13, IL-6, IL-8, TNFα and ICAM-1. Additionally RNO reversed the reduction of Nrf2, HO-1 and GPx mRNA levels and consequently restored the TAC and reduced the H2O2 formation. RNO inhibits RSV infection of WD-HBE cultures and mitigates the cytopathological changes associated to this virus.

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Section: Introductionmentioning

confidence: 99%

Roflumilast Inhibits Respiratory Syncytial Virus Infection in Human Differentiated Bronchial Epithelial Cells

et al. 2013

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“…mode of administration in hospital settings (4). New therapeutic interventions able to lower the viral load, decrease transmission, and prevent lower respiratory complications are needed.RSV infection is initiated by attachment of the viral G protein to the surface of airway epithelial (AE) cells (5,6). Following attachment, the viral F protein mediates fusion of the viral and cellular membranes, allowing the RSV ribonucleic protein (RNP) complex, comprised of the viral RNA genome encapsulated with nucleoprotein (N) and associated with the phosphoprotein (P) and RNA-dependent RNA polymerase (L), to enter the cytoplasm.…”

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confidence: 99%

The Interferon Type I/III Response to Respiratory Syncytial Virus Infection in Airway Epithelial Cells Can Be Attenuated or Amplified by Antiviral Treatment

McCutcheon

Jordan

Mawhorter

et al. 2016

J Virol

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Human respiratory syncytial virus (RSV) is a single-stranded RNA virus that causes acute, and occasionally fatal, lower respiratory illness in young infants, the elderly, and immunocompromised patients. Therapeutic interventions able to cut short viral replication and quickly return the airways to normal function are needed. An understanding of antiviral activities and their effects on host defense mechanisms is important for the design of safe and effective therapy. We targeted functionally and temporally distinct steps within the viral life cycle using small-molecule RSV inhibitors and studied their antiviral activities and their effects on innate interferon responses of airway epithelial cells in vitro. H uman respiratory syncytial virus (RSV) is a single-stranded, negative-sense RNA virus belonging to the family Paramyxoviridae. Premature and very young infants are at the highest risk of having severe lower respiratory tract infections and, later, a higher incidence of chronic asthma (1). Older adults with chronic lung or heart disease and individuals with suppressed immune systems also often require medical care after RSV infection. The lack of long-lasting protection after primary infection contributes to the capacity of RSV to cause yearly outbreaks and has challenged vaccine development (2). Synagis, a monoclonal antibody (MAb) directed against the RSV fusion protein, has shown prophylactic utility, but its cost and intramuscular route of administration have limited its use to hospitalized, high-risk infants Ͻ2 years of age (2). The only therapeutic intervention for RSV infection currently available to patients is the use of ribavirin (3), but its use is also limited because of poor efficacy and teratogenicity and the requirement of an aerosol and/or intravenous (i.v.) mode of administration in hospital settings (4). New therapeutic interventions able to lower the viral load, decrease transmission, and prevent lower respiratory complications are needed.RSV infection is initiated by attachment of the viral G protein to the surface of airway epithelial (AE) cells (5,6). Following attachment, the viral F protein mediates fusion of the viral and cellular membranes, allowing the RSV ribonucleic protein (RNP) complex, comprised of the viral RNA genome encapsulated with nucleoprotein (N) and associated with the phosphoprotein (P) and RNA-dependent RNA polymerase (L), to enter the cytoplasm. The RNP complex performs viral transcription to produce capped and polyadenylated mRNAs and genome replication. Detailed understanding of RSV biology is made difficult by the intimate coupling of transcription and replication activities. Furthermore, the RSV polymerase is large and complex, containing multiple domains and enzymatic activities that allow it to function and be

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“…Receptors of innate immune recognition, like Toll-like receptors (TLRs) and retinoic acid-inducible gene I (RIG-I), which are involved in detection of viral RNA, promote the activation of antiviral immunity and cytokine production, as well as the recruitment of proinflammatory cells (10,(13)(14)(15)(16). This increased expression of inflamma-tory mediators, immune cell chemoattractants, and antigen-processing machinery is implicated in RSV-induced lung injury (13,(17)(18)(19). Indeed, several gene-based studies have linked the differences in outcomes after RSV infection to genes involved in immune responses, including those for interleukin 4 (IL-4), IL-6, and IL-8, as well as TLR4, in innate immunity (20).…”

mentioning

confidence: 99%

Respiratory Syncytial Virus Infection Upregulates NLRC5 and Major Histocompatibility Complex Class I Expression through RIG-I Induction in Airway Epithelial Cells

Guo

Liu

Shi

et al. 2015

J Virol

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Respiratory syncytial virus (RSV) is the leading cause of acute respiratory tract viral infection in infants, causing bronchiolitis and pneumonia. The host antiviral response to RSV acts via retinoic acid-inducible gene I (RIG-I). We show here that RSV infection upregulates major histocompatibility complex class I (MHC-I Respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract infection in infants and young children, causing bronchiolitis and pneumonia in infants and young children worldwide. Due to the highly infectious nature of the virus, roughly two-thirds of children are infected by their first birthday, and this reaches essentially 100% by the age of 2 (1, 2). RSV infection is a leading cause of infant hospitalization due to bronchiolitis (2, 3). In the United States alone, an estimated 2.1 million children under 5 years of age with RSV infection require medical attention each year (4). Importantly, lower respiratory tract infection by RSV early in life is a risk factor for persistent wheezing and asthma in later life (5, 6). There are no RSV vaccines available to prevent childhood infection. These factors create an urgent need to understand the mechanisms of RSV disease, the molecular mechanisms associated with immunoregulation, and the downstream association between RSV infection and allergic asthma.RSV belongs to the subfamily Pneumovirinae of the paramyxoviruses. A negative-sense, single-stranded RNA virus with a genome of approximately 15,000 nucleotides (7), the virus can infect a broad range of cells. In patients, however, infection is normally highly restricted to the superficial cells of the respiratory epithelium, the ciliated cells of the small bronchioles, and pneumocytes in the alveoli (8-10). Infection is initiated by cell surface binding via proteoglycans (11), followed by nucleolin-mediated fusion for RSV cell entry (9, 12) and infection. In response, the host initiates an early innate immune response at the site of infection. Receptors of innate immune recognition, like Toll-like receptors (TLRs) and retinoic acid-inducible gene I (RIG-I), which are involved in detection of viral RNA, promote the activation of antiviral immunity and cytokine production, as well as the recruitment of proinflammatory cells (10,(13)(14)(15)(16). This increased expression of inflamma-

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Advances in understanding respiratory syncytial virus infection in airway epithelial cells and consequential effects on the immune response

Cited by 54 publications

References 83 publications

Roflumilast Inhibits Respiratory Syncytial Virus Infection in Human Differentiated Bronchial Epithelial Cells

Roflumilast Inhibits Respiratory Syncytial Virus Infection in Human Differentiated Bronchial Epithelial Cells

The Interferon Type I/III Response to Respiratory Syncytial Virus Infection in Airway Epithelial Cells Can Be Attenuated or Amplified by Antiviral Treatment

Respiratory Syncytial Virus Infection Upregulates NLRC5 and Major Histocompatibility Complex Class I Expression through RIG-I Induction in Airway Epithelial Cells

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