Activation and Inhibition of Apoptotic Pathways by SV5

Summary

Principal Investigator: Biao He
Abstract: The paramyxovirus family includes emerging viruses such as Hendra virus and Nipah virus as well as many important human and animal pathogens such as respiratory syncytial virus, measles virus, imumps virus and Newcastle disease virus. Apoptosis play an important role in the pathogenesis of paramyxoviruses, but the mechanisms of activation and inhibition of apoptotic pathways by paramyxoviruses are not well understood. Simian virus 5 (SV5), a paramyxovirus, does not cause apoptosis but a mutant SV5 without the 44-amino-acid-residue small hydrophobic (SH) gene (rSV5deltaSH) induces apoptosis. In preliminary studies, increased expression levels of tumor necrosis factor alpha (TNF) were detected in rSV5deltaSH-infected cells and TNF played an essential role in inducing apoptosis. It is hypothesized that the SH protein blocks TNF-induced apoptotic pathways and the SH protein may define a new anti-apoptosis mechanism. The long term goal of this work is to understand how paramyxoviruses interact with host cell apoptotic pathways. The proposal focuses on following aims: (1) investigate the mechanism of inhibition of TNF signaling pathways by the SH protein. In preliminary studies, the SH protein was sufficient to inhibit TNF signaling. Key residues of SH that are important for its inhibitory effect and host cell proteins with which SH interacts will be identified; (2) investigate the mechanism of activation of TNF expression in rSV5deltaSH-infected cells. Expression of TNF in virus infected cells will be examined at the mRNA and protein levels. SV5 proteins responsible for activating expression will be identified; (3) study anti-apoptosis functions of SH proteins encoded by other paramyxov ruses. SV5 containing SH genes from other paramyxoviruses in place of the SH gene of SV5 will be generated _and examined for their abilities to induce apoptosis. Understanding the roles played by viral proteins lin activating and inhibiting apoptosis will provide new insights on paramyxovirus pathogenesis and may lead to new targets for anti-viral therapy and new strategies for vaccine development.
Funding Period: 2003-07-01 - 2008-12-31
more information: NIH RePORT

Top Publications

  1. pmc Phosphorylation of paramyxovirus phosphoprotein and its role in viral gene expression
    Sandra M Fuentes
    Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA 16802, USA
    Future Microbiol 5:9-13. 2010
  2. pmc AKT1-dependent activation of NF-kappaB by the L protein of parainfluenza virus 5
    Priya Luthra
    Department of Veterinary and Biomedical Sciences, Intercollege Graduate Program in Cell and Developmental Biology, Pennsylvania State University, University Park, Pennsylvania 16802, USA
    J Virol 82:10887-95. 2008
  3. pmc A single amino acid residue change in the P protein of parainfluenza virus 5 elevates viral gene expression
    Khalid A Timani
    Center of Molecular Immunology and Infectious Disease, Department of Veterinary and Biomedical Sciences, Pennsylvania State University, University Park, PA 16802, USA
    J Virol 82:9123-33. 2008
  4. pmc Akt plays a critical role in replication of nonsegmented negative-stranded RNA viruses
    Minghao Sun
    Center of Molecular Immunology and Infectious Disease, Department of Veterinary and Biomedical Sciences, Pennsylvania State University, 115 Henning Bldg, University Park, PA 16802, USA
    J Virol 82:105-14. 2008
  5. pmc Inhibition of interleukin-6 expression by the V protein of parainfluenza virus 5
    Yuan Lin
    Department of Veterinary and Biomedical Sciences, Pennsylvania State University, University Park, PA 16802, USA
    Virology 368:262-72. 2007
  6. pmc Replacement of the respiratory syncytial virus nonstructural proteins NS1 and NS2 by the V protein of parainfluenza virus 5
    Kim C Tran
    Department of Biochemistry and Molecular Biology, Pennsylvania State University, 406 South Frear, University Park, PA 16802, USA
    Virology 368:73-82. 2007
  7. pmc Function of the respiratory syncytial virus small hydrophobic protein
    Sandra Fuentes
    Center of Molecular Immunology and Infectious Disease, Department of Veterinary and Biomedical Sciences, Pennsylvania State University, 115 Henning Bldg, University Park, PA 16802, USA
    J Virol 81:8361-6. 2007
  8. pmc Recombinant parainfluenza virus 5 (PIV5) expressing the influenza A virus hemagglutinin provides immunity in mice to influenza A virus challenge
    S Mark Tompkins
    Department of Infectious Diseases, University of Georgia, Athens, GA, USA
    Virology 362:139-50. 2007
  9. pmc Function of small hydrophobic proteins of paramyxovirus
    Rebecca L Wilson
    Center of Molecular Immunology and Infectious Disease, Department of Veterinary and Biomedical Sciences, Pennsylvania State University, 115 Henning Bldg, University Park, PA 16802, USA
    J Virol 80:1700-9. 2006
  10. ncbi The role of simian virus 5 V protein on viral RNA synthesis
    Yuan Lin
    Department of Veterinary Science, Pennsylvania State University, University Park, PA 16802, USA
    Virology 338:270-80. 2005

Scientific Experts

  • Sandra M Fuentes
  • Biao He
  • Yuan Lin
  • Minghao Sun
  • Dengyun Sun
  • Khalid A Timani
  • Priya Luthra
  • Michael N Teng
  • S Mark Tompkins
  • Kim C Tran
  • Rebecca L Wilson
  • Khalid Timani
  • Phuong Tieu Schmitt
  • Celia Keim
  • Anthony P Schmitt
  • Chris Murphy
  • Matthew Wolfgang
  • Avery August
  • Mary J Kennett
  • Kari A Kramer
  • Jie Xu
  • Joan E Durbin
  • George P Leser
  • Terri Rothermel
  • Debra L Haas
  • Celia D Keim
  • Robert A Lamb
  • Ralph Tripp
  • Russell K Durbin
  • Elizabeth W Howerth
  • Alicia Klatt
  • Ping Wang
  • Andrew J Henderson
  • Erica C Taddeo
  • Frank Horvath
  • Jason A Aligo
  • Rebecca Wilson

Detail Information

Publications10

  1. pmc Phosphorylation of paramyxovirus phosphoprotein and its role in viral gene expression
    Sandra M Fuentes
    Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA 16802, USA
    Future Microbiol 5:9-13. 2010
    ....
  2. pmc AKT1-dependent activation of NF-kappaB by the L protein of parainfluenza virus 5
    Priya Luthra
    Department of Veterinary and Biomedical Sciences, Intercollege Graduate Program in Cell and Developmental Biology, Pennsylvania State University, University Park, Pennsylvania 16802, USA
    J Virol 82:10887-95. 2008
    ..Furthermore, we have found that L interacts with AKT1 and enhances its phosphorylation. We speculate that L may encode AKT1 kinase activity...
  3. pmc A single amino acid residue change in the P protein of parainfluenza virus 5 elevates viral gene expression
    Khalid A Timani
    Center of Molecular Immunology and Infectious Disease, Department of Veterinary and Biomedical Sciences, Pennsylvania State University, University Park, PA 16802, USA
    J Virol 82:9123-33. 2008
    ..Based on these results, we propose that phosphorylation of the P protein at residue 157 plays an important role in regulating viral RNA replication...
  4. pmc Akt plays a critical role in replication of nonsegmented negative-stranded RNA viruses
    Minghao Sun
    Center of Molecular Immunology and Infectious Disease, Department of Veterinary and Biomedical Sciences, Pennsylvania State University, 115 Henning Bldg, University Park, PA 16802, USA
    J Virol 82:105-14. 2008
    ..The finding that Akt plays a critical role in replication of NNSV will lead to a better understanding of how these viruses replicate, as well as novel strategies to treat infectious diseases caused by NNSVs...
  5. pmc Inhibition of interleukin-6 expression by the V protein of parainfluenza virus 5
    Yuan Lin
    Department of Veterinary and Biomedical Sciences, Pennsylvania State University, University Park, PA 16802, USA
    Virology 368:262-72. 2007
    ..Using reporter gene assays and chromatin immunoprecipitation (ChIP), it was found that NF-kappaB played an important role in activating expression of IL-6. We have proposed a model of activating and inhibiting IL-6 transcription by PIV5...
  6. pmc Replacement of the respiratory syncytial virus nonstructural proteins NS1 and NS2 by the V protein of parainfluenza virus 5
    Kim C Tran
    Department of Biochemistry and Molecular Biology, Pennsylvania State University, 406 South Frear, University Park, PA 16802, USA
    Virology 368:73-82. 2007
    ..These data indicate that V was able to replace some of the IFN inhibitory functions of the RSV NS1 and NS2 proteins, but also that NS1 and NS2 have functions in viral replication beyond IFN antagonism...
  7. pmc Function of the respiratory syncytial virus small hydrophobic protein
    Sandra Fuentes
    Center of Molecular Immunology and Infectious Disease, Department of Veterinary and Biomedical Sciences, Pennsylvania State University, 115 Henning Bldg, University Park, PA 16802, USA
    J Virol 81:8361-6. 2007
    ..The results indicate that the SH protein of RSV has a function similar to that of PIV5 SH and that it can inhibit TNF-alpha signaling...
  8. pmc Recombinant parainfluenza virus 5 (PIV5) expressing the influenza A virus hemagglutinin provides immunity in mice to influenza A virus challenge
    S Mark Tompkins
    Department of Infectious Diseases, University of Georgia, Athens, GA, USA
    Virology 362:139-50. 2007
    ..The efficacy of rPIV5-H3 as a live vaccine was examined in 6-week-old BALB/c mice. The results show that a single dose inoculation provides broad and considerable immunity against influenza A virus infection...
  9. pmc Function of small hydrophobic proteins of paramyxovirus
    Rebecca L Wilson
    Center of Molecular Immunology and Infectious Disease, Department of Veterinary and Biomedical Sciences, Pennsylvania State University, 115 Henning Bldg, University Park, PA 16802, USA
    J Virol 80:1700-9. 2006
    ..Furthermore, both ectopically expressed SV5 SH and MuV SH blocked activation of NF-kappaB by TNF-alpha in a reporter gene assay, suggesting that both SH proteins can inhibit TNF-alpha signaling...
  10. ncbi The role of simian virus 5 V protein on viral RNA synthesis
    Yuan Lin
    Department of Veterinary Science, Pennsylvania State University, University Park, PA 16802, USA
    Virology 338:270-80. 2005
    ..The V protein inhibited luciferase expression from the mini-genome with a defective AGP, suggesting V inhibits SV5 transcription. Thus, SV5 V inhibits both SV5 RNA replication and transcription...