Respiratory syncytial virus infection activates STAT signaling in human epithelial cells

Kong, Xiaoyuan; Juan, Homero San; Kumar, Mukesh; Behera, Aruna K.; Mohapatra, Alexander; Hellermann, Gary; Mane, S.S.; Lockey, Richard F.; Mohapatra, Shyam S.

doi:10.1016/s0006-291x(03)01008-8

Cited by 40 publications

(33 citation statements)

References 29 publications

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“…Three other studies reported analyses of in vivo gene expression in blood of RSV-infected children and adults (9,10,44). In addition, several in vitro studies in epithelial cells have been performed (18,26,28,45). To our knowledge, our study is the first to focus on the secondary immune response to RSV infection or challenge after vaccination in lungs of mice using microarrays.…”

Section: Discussionmentioning

confidence: 93%

Gene Expression Differences in Lungs of Mice during Secondary Immune Responses to Respiratory Syncytial Virus Infection

Schuurhof

Bont

Pennings³

et al. 2010

J Virol

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Vaccine-induced immunity has been shown to alter the course of a respiratory syncytial virus (RSV) infection both in murine models and in humans. To elucidate which mechanisms underlie the effect of vaccine-induced immunity on the course of RSV infection, transcription profiles in the lungs of RSV-infected mice were examined by microarray analysis. Three models were used: RSV reinfection as a model for natural immunity, RSV challenge after formalin-inactivated RSV vaccination as a model for vaccine-enhanced disease, and RSV challenge following vaccination with recombinant RSV virus lacking the G gene (⌬G-RSV) as a model for vaccine-induced immunity. Gene transcription profiles, histopathology, and viral loads were analyzed at 1, 2, and 5 days after RSV challenge. On the first 2 days after challenge, all mice displayed an expression pattern in the lung similar of that found in primary infection, showing a strong innate immune response. On day 5 after RSV reinfection or after challenge following ⌬G-RSV vaccination, the innate immune response was waning. In contrast, in mice with vaccine-enhanced disease, the innate immune response 5 days after RSV challenge was still present even though viral replication was diminished. In addition, only in this group was Th2 gene expression induced. These findings support a hypothesis that vaccine-enhanced disease is mediated by prolonged innate immune responses and Th2 polarization in the absence of viral replication.Respiratory syncytial virus (RSV) infection in infants can cause morbidity ranging from mild upper respiratory tract symptoms to severe bronchiolitis and even mortality (29). A small proportion of infected infants need hospitalization, whereas the majority develop only upper respiratory tract infection and recover in an outpatient setting (14). Known risk factors for more severe disease in children are age younger than 3 months, preterm birth, chronic lung disease of prematurity, congenital heart disease, Down's syndrome, cystic fibrosis, and immunodeficiency disorders (1,30,37). Besides infants, specific adult populations also are at risk to develop severe RSV infection, such as adults who are immunocompromised, aged, or institutionalized or have underlying diseases (8, 13). Both immunological mechanisms and virus-induced cytopathology may be keys to the variable severity of RSV bronchiolitis in infancy. The association between naturally occurring polymorphisms in innate immune response genes and the susceptibility to severe RSV bronchiolitis supports this theory (15,16,20,32).Murine models are widely used to study RSV-induced pathology. However, differences in RSV pathogenesis in relation to the genetic background of the mouse strain used have been described (19). These murine models have shown that a complex immune response is induced by RSV infection. However, high viral titers are needed to induce consistent histopathological changes in the lung (12). Generally, mice clear the virus without suffering severe lung pathology. Vaccination of mice with formalin-inac...

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Section: Discussionmentioning

confidence: 93%

Gene Expression Differences in Lungs of Mice during Secondary Immune Responses to Respiratory Syncytial Virus Infection

Schuurhof

Bont

Pennings³

et al. 2010

J Virol

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“…For example, DN-PKC-␣ reduced the expression of luciferase dependent on the transcriptional activation of a promoter driven by the serum response element by 50% (40). In addition, other signaling molecules reportedly activated during RSV infection (18,19) might be acting in concert with PKC during the initial infection process.…”

Section: Discussionmentioning

confidence: 99%

“…It was previously reported that RSV requires functional MEK-ERK1/2 and Stat1 pathways for successful infection (18,19). Because of the potential link between PKC and ERK (21) and since PKC plays a central role in signaling events leading to changes in the cell membrane and cytoskeleton, including caveolae and lipid raft formation (27), we hypothesized that PKC activation plays a role in the early stages of RSV infection, especially RSV fusion.…”

mentioning

confidence: 99%

Protein Kinase C-α Activity Is Required for Respiratory Syncytial Virus Fusion to Human Bronchial Epithelial Cells

San‐Juan‐Vergara

Peeples

Lockey

et al. 2004

J Virol

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Respiratory syncytial virus (RSV) infection activates protein kinase C (PKC), but the precise PKC isoform(s) involved and its role(s) remain to be elucidated. On the basis of the activation kinetics of different signaling pathways and the effect of various PKC inhibitors, it was reasoned that PKC activation is important in the early stages of RSV infection, especially RSV fusion and/or replication. Herein, the role of PKC-␣ during the early stages of RSV infection in normal human bronchial epithelial cells is determined. The results show that the blocking of PKC-␣ activation by classical inhibitors, pseudosubstrate peptides, or the overexpression of dominant-negative mutants of PKC-␣ in these cells leads to significantly decreased RSV infection. RSV induces phosphorylation, activation, and cytoplasm-to-membrane translocation of PKC-␣. Also, PKC-␣ colocalizes with virus particles and is required for RSV fusion to the cell membrane. Thus, PKC-␣ could provide a new pharmacological target for controlling RSV infection.Respiratory syncytial virus (RSV), a pneumovirus, is an important respiratory pathogen that produces an annual epidemic of respiratory illness which is seen primarily in infants, but also in adults, worldwide (39). Effective vaccines against RSV are not currently available. The development of antivirals requires a comprehensive molecular understanding of the early events of virus-host interaction necessary for virus fusion and entry into cells, an understanding which is lacking. RSV activates multiple signaling pathways (1, 2, 8, 13), including those involving protein kinase C (PKC), which appear to play a role in acute inflammation (1,29). However, the role of PKC in RSV infection is poorly understood.PKC comprises a family of serine/threonine kinases with at least 12 members. In general, PKC has a catalytic domain, which also contains the ATP binding site, and a regulatory domain containing the phospholipid and diacylglycerol (DAG) binding site. On the basis of structure and activation requirements, the PKC family can be divided into the following major subclasses: (i) classical PKCs, comprising the ␣, ␤I, ␤II, and ␥ isozymes that are Ca 2ϩ dependent and DAG sensitive; (ii) novel PKCs, comprising the ␦, ε, , , and isozymes that are Ca 2ϩ independent and DAG sensitive; (iii) atypical PKCs, comprising the and / isozymes that are Ca 2ϩ independent and DAG insensitive; and (iv) the PKC-isozyme that is similar to the atypical isozymes but contains an additional specific signal peptide transmembrane domain (28, 32). PKCs play an important role in infection of mammalian cells by different viruses (9,10,30,31,33,38). PKC inhibitors reduce the entry of intracellular mature vaccinia virus by affecting Rac1 activation and actin assembly (44). PKC is also important in the formation of caveolae, which a number of viruses such as human immunodeficiency virus type 1, filoviruses (Ebola), and simian virus 40 (11) utilize to evade the phagolysosomal pathway, thus allowing them to thrive inside cells by indirectly eva...

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“…On the other hand, another group has suggested that nuclear factor-B has no effect to regulate surfactant protein gene expression (47). Recent work from Kong et al (27) has shown that in human A549 alveolar epithelial cells, RSV induced phosphorylation and nuclear translocation of signal transducer and activator of transcription (STAT)-1␣. RSV also activated STAT-3 and IL-6.…”

Section: Discussionmentioning

confidence: 99%

Effects of RSV infection on pulmonary surfactant protein SP-A in cultured human type II cells: contrasting consequences on SP-A mRNA and protein

Alcorn

Stark

Chiappetta

et al. 2005

American Journal of Physiology-Lung Cellular and Molecular Phys

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Alterations in surfactant protein homeostasis in the lung may result from changes in production, metabolism, or uptake of the protein within the lung. We hypothesized that RSV infection of the type II cell, the primary source of surfactant protein, may alter surfactant protein gene expression. Human type II cells grown in primary culture possess lamellar bodies (a type II cell-specific organelle) and the ability to express surfactant protein mRNA. These cells were infected with RSV (by morphology and antibody binding). Surfactant protein mRNA levels determined by quantitative RT-PCR indicated a marked increase in SP-A mRNA levels (3-fold) 24 h after RSV exposure, whereas SP-D mRNA levels were unaffected. In contrast to mRNA levels, total SP-A protein levels (determined by Western blot analysis) were decreased 40% after RSV infection. The percentage of secreted SP-A was 43% of the total SP-A in the RSV-infected cells, whereas the percentage of secreted SP-A was 61% of the total SP-A in the uninfected cells. These changes in SP-A transcript levels and protein secretion in cultured human cells were recapitulated in RSV-infected mouse lung. Our findings suggest that type II cells are potentially important targets of RSV lower respiratory infection and that alterations in surfactant protein gene expression and SP-A protein homeostasis in the lung may arise via direct effects of RSV. surfactant protein A; respiratory syncytial virus; alveolar type II cell RESPIRATORY SYNCYTIAL VIRUS (RSV) is the most important cause of serious lower respiratory illness and viral lower respiratory tract disease in infants and children (55), primarily resulting in bronchiolitis and pneumonia, and often the distinctions between these two infections are blurred. Epidemiological studies have demonstrated the extent of infection by RSV: 50% of children will acquire RSV during the first year of life, 40% of these will develop lower respiratory tract disease, and 1% will require hospitalization. By 3 yr of age, every child will have been infected with RSV at least once (14,15,40,41,45). Lower respiratory infections (LRI) caused by respiratory syncytial virus are common occurrences in early childhood. Several epidemiological studies in children and recent laboratory investigations in animal models suggest an association between LRIs (including RSV infection) and allergic sensitization or persistent/recurrent respiratory obstruction (1, 3-5, 14, 15, 41, 46). Viral LRIs appear to make infants and children more susceptible to superinfection by pathogenic bacteria (30,31,42). Increased frequencies of infection caused by Hemophilus influenzae (6, 53), meningococcus (52), and Staphylococcus aureus (6, 9) have been associated with recent RSV infection, causing otitis media, pneumonia, and meningitis. These data suggest that viral infection alters normal lung responses to a subsequent "challenge." The causative relationship between RSV LRI and bacterial superinfection has been demonstrated in animal models of cotton rats (46) and sheep (3)(4)(5)8). T...

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Respiratory syncytial virus infection activates STAT signaling in human epithelial cells

Cited by 40 publications

References 29 publications

Gene Expression Differences in Lungs of Mice during Secondary Immune Responses to Respiratory Syncytial Virus Infection

Gene Expression Differences in Lungs of Mice during Secondary Immune Responses to Respiratory Syncytial Virus Infection

Protein Kinase C-α Activity Is Required for Respiratory Syncytial Virus Fusion to Human Bronchial Epithelial Cells

Effects of RSV infection on pulmonary surfactant protein SP-A in cultured human type II cells: contrasting consequences on SP-A mRNA and protein

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