Host cell signaling in response to RSV infection

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Title: Host cell signaling in response to RSV infection
Author: Ping Liu
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
URI: http : / /hdl .handle .net /2152 .3 /106
Date: 2008-04-14

Citation

Host cell signaling in response to RSV infection. Doctoral dissertation, The University of Texas Medical Branch. Available electronically from http : / /hdl .handle .net /2152 .3 /106 .

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