Host cell signaling in response to RSV infection

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Host cell signaling in response to RSV infection

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dc.contributor.advisor Edward B. Thompson en_US
dc.creator Ping Liu en_US
dc.date.accessioned 2011-12-20T16:04:40Z
dc.date.available 2008-06-17 en_US
dc.date.available 2011-12-20T16:04:40Z
dc.date.created 2008-04-28 en_US
dc.date.issued 2008-04-14 en_US
dc.identifier.other etd-04282008-143115 en_US
dc.identifier.uri http://hdl.handle.net/2152.3/106
dc.description.abstract RSV infection is the most important cause of hospitalization of infants, and is also the major cause for admissions in adults with chronic cardiac disease and pulmonary diseases. So far, there is no effective treatment or vaccine against RSV infection. Intensive studies have been performed to understand mechanisms and consequences of RSV-induced host cell signaling. My dissertation project provides three major contributions to this field.\r\nFirstly, I found that retinoic acid-inducible gene I (RIG-I) and Toll like receptor 3 (TLR3) play distinct roles in mediating RSV-induced innate immune responses. Short interfering RNA (siRNA)-mediated RIG-I \"knockdown\" significantly inhibited the translocation of nuclear factor-kappa B (NF-kappa B) and interferon response factor 3 (IRF3) to the nucleus at the early phase of viral infection. In contrast, siRNA-mediated TLR3 knockdown did not affect RSV-induced NF-kappa B binding to DNA but block the activating phosphorylation of NF-kappa B /RelA at serine residue 276.\r\nSecondly, I first demonstrated that RIG-I was involved in the activation of NIK/IKK alpha complex, two key noncanonical kinases that induce the protelytic processing of an I kappa B alpha-like inhibitor p100 to p52. I also proved that a fraction of RelA was associated with cytoplasmic p100. In addition, the RSV-induced proteolysis of p100 not only produces p52, but also releases RelA and increases its nuclear translocation. This finding suggested that part of the RelA activation in response to RSV infection was induced by the NIK/IKK alpha complex. Because inhibition of NIK/IKK alpha does not affect RSV replication but reduces inflammatory chemokine production, this protein complex could be a good target for drug treatment of RSV infection.\r\nThirdly, our previous study has reported the existence of IKK gamma delta, a splicing variant of IKK gamma, which excludes exon 5. I compared the function of IKK gamma and IKK gamma delta in response to ssRNA viruses. I found that in contrast to IKK gamma, which is essential for both NF-kappa B and IRF3 activation, IKK gamma delta failed to activate IRF3 in response to either Sendai virus or respiratory syncytial virus (RSV). However, IKK gamma delta mediated NF- kappa B activation was intact. I demonstrated that the missing region of IKK gamma delta made it unable to recruit TANK, a key factor that recruits atypical IKKs to activate the IRF3 pathway. \r\n en_US
dc.format.medium electronic en_US
dc.language.iso eng en_US
dc.rights Copyright © is held by the author. Presentation of this material on the TDL web site by The University of Texas Medical Branch at Galveston was made possible under a limited license grant from the author who has retained all copyrights in the works. en_US
dc.subject RSV en_US
dc.subject RIG-I en_US
dc.subject NIK en_US
dc.subject MAVS en_US
dc.subject IKK gamma delta en_US
dc.subject host cell signaling en_US
dc.title Host cell signaling in response to RSV infection en_US
dc.type.material text en_US
dc.type.genre dissertation en_US
thesis.degree.name PhD en_US
thesis.degree.level Doctoral en_US
thesis.degree.grantor The University of Texas Medical Branch en_US
thesis.degree.department Human Biological Chemistry and Genetics en_US
dc.contributor.committeeMember Stokes Peebles en_US
dc.contributor.committeeMember Roberto P. Garofalo en_US
dc.contributor.committeeMember Kui Li en_US
dc.contributor.committeeMember Allan R. Brasier en_US

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