title: Effects of nonstructural proteins NS1 and NS2 of human respiratory syncytial virus on interferon regulatory factor 3, NF-kappaB, and proinflammatory cytokines.
abstract: Human respiratory syncytial virus (HRSV) is the leading cause of serious pediatric acute respiratory tract infections, and a better understanding is needed of the host response to HRSV and its attenuated vaccine derivatives. It has been shown previously that HRSV nonstructural proteins 1 and 2 (NS1 and NS2) inhibit the induction of alpha/beta interferon (IFN-alpha/beta) in A549 cells and human macrophages. Two principal transcription factors for the early IFN-beta and -alpha1 response are interferon regulatory factor 3 (IRF-3) and nuclear factor kappaB (NF-kappaB). At early times postinfection, wild-type HRSV and the NS1/NS2 deletion mutants were very similar in the ability to activate IRF-3. However, once NS1 and NS2 were expressed significantly, they acted cooperatively to suppress activation and nuclear translocation of IRF-3. Since these viruses differed greatly in the induction of IFN-alpha/beta, NF-kappaB activation was evaluated in Vero cells, which lack the structural genes for IFN-alpha/beta and would preclude confounding effects of IFN-alpha/beta. This showed that deletion of the NS2 gene sharply reduced the ability of HRSV to induce activation of NF-kappaB. Since recombinant HRSVs from which the NS1 or NS2 genes have been deleted are being developed as vaccine candidates, we investigated whether the changes in activation of host transcription factors and increased IFN-alpha/beta production had an effect on the epithelial production of proinflammatory factors. Viruses lacking NS1 and/or NS2 stimulated modestly lower production of RANTES (Regulated on Activation Normal T-cell Expressed and Secreted), interleukin 8, and tumor necrosis factor alpha compared to wild-type recombinant RSV, supporting their use as attenuated vaccine candidates.
authors.affiliation: Laboratory of Infectious Diseases, NIAID, Building 50, Room 6503, 50 South Dr., MSC 8007, Bethesda, MD 20892-8007, USA.
authors.forename: Kirsten M
authors.initials: KM
authors.lastname: Spann
authors.forename: Kim C
authors.initials: KC
authors.lastname: Tran
authors.forename: Peter L
authors.initials: PL
authors.lastname: Collins
mesh_terms: D000818:Animals; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D018946:Chemokine CCL5 / Q000096:biosynthesis; D002522:Chlorocebus aethiops; D016207:Cytokines / Q000096:biosynthesis*; D004268:DNA-Binding Proteins / Q000096:biosynthesis*; D006801:Humans; D050838:Interferon Regulatory Factor-3; D016209:Interleukin-8 / Q000096:biosynthesis; D016328:NF-kappa B / Q000096:biosynthesis*; D018113:Respiratory Syncytial Virus, Human / Q000502:physiology*; D013997:Time Factors; D014157:Transcription Factors / Q000096:biosynthesis*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D014709:Vero Cells; D017361:Viral Nonstructural Proteins / Q000502:physiology*
chemical_list: D018946:Chemokine CCL5; D016207:Cytokines; D004268:DNA-Binding Proteins; C494232:IRF3 protein, human; D050838:Interferon Regulatory Factor-3; D016209:Interleukin-8; D016328:NF-kappa B; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D017361:Viral Nonstructural Proteins