TOGAVIRUS TROPISM FOR BONES, JOINTS, AND CNS

Summary

Principal Investigator: Mark Heise
Abstract: Virus-induced inflammatory diseases, including arthritis, pneumonia, and encephalitis, are a significant cause of human disease, and there is a clear need to improve our overall understanding of the pathogenesis of this diverse array of conditions. Togaviruses, which include the mosquito-borne alphaviruses such as Chikungunya, O'nyong-nyong, and Ross River virus cause massive outbreaks of infectious arthritis/athralgia/myalgia affected thousands to millions of individuals and continue to be an emerging threat. However, even though these viruses can cause severe rheumatic disease on a massive scale, relatively little is known about their pathogenesis. We and others have developed a mouse model of RRV-induced arthritis and myositis, where the virus replicates to high levels in the synovial joints and skeletal muscle, but virus induced disease is dependent on an immunopathologic inflammatory response largely comprised of macrophages. Studies on the host factors that regulate this response demonstrated that activation of the host complement cascade is required for the development of virus-induced tissue destruction, but not recruitment of inflammatory cells into the virus-infected tissues. Therefore, the objectives of this proposal are to investigate the role that complement plays in the pathogenesis of RRV- induced disease, including analysis of the mechanisms by which RRV infection activates the complement system and the downstream functions of complement in regulating the immunopathologic inflammatory response. We also propose to extend these studies from the mouse model back to the human disease in order to determine whether complement activation is a component of the virus-induced inflammatory response in individuals suffering from alphavirus-induced arthritis. Therefore, this work will significantly enhance our understanding of the pathogenesis of Togavirus-induced arthritis/myalgia, while also providing insights into novel viral interactions with the host complement cascade and inflammatory response that may ultimately lead to better understanding of the mechanisms that regulate other pathologic virus-induced inflammatory responses, such as occur in viral arthritis, encephalitis, or pneumonia.
Funding Period: ----------------2000 - ---------------2011-
more information: NIH RePORT

Top Publications

  1. pmc Characterization of Ross River virus tropism and virus-induced inflammation in a mouse model of viral arthritis and myositis
    Thomas E Morrison
    Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
    J Virol 80:737-49. 2006
  2. pmc Myd88-dependent toll-like receptor 7 signaling mediates protection from severe Ross River virus-induced disease in mice
    Lauren M Neighbours
    Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
    J Virol 86:10675-85. 2012
  3. pmc An attenuating mutation in a neurovirulent Sindbis virus strain interacts with the IPS-1 signaling pathway in vivo
    Amy C Wollish
    Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA
    Virology 435:269-80. 2013
  4. pmc Complement receptor 3 promotes severe ross river virus-induced disease
    Thomas E Morrison
    The Carolina Vaccine Institute, University of North Carolina at Chapel Hill, 9024 Burnett Womack, CB 7292, Manning Drive, Chapel Hill, NC 27599
    J Virol 82:11263-72. 2008
  5. ncbi The host complement system and arbovirus pathogenesis
    T E Morrison
    Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA
    Curr Drug Targets 9:165-72. 2008
  6. pmc Complement contributes to inflammatory tissue destruction in a mouse model of Ross River virus-induced disease
    Thomas E Morrison
    Department of Genetics, University of North Carolina at Chapel Hill, NC 27599, USA
    J Virol 81:5132-43. 2007
  7. pmc Differential induction of type I interferon responses in myeloid dendritic cells by mosquito and mammalian-cell-derived alphaviruses
    Reed S Shabman
    Department of Genetics, The Carolina Vaccine Institute, The University of North Carolina, Chapel Hill, NC 27599, USA
    J Virol 81:237-47. 2007
  8. pmc Modulation of cellular tropism and innate antiviral response by viral glycans
    Kristin M Rogers
    Department of Genetics, Carolina Vaccine Institute, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
    J Innate Immun 1:405-12. 2009
  9. pmc A mouse model of chikungunya virus-induced musculoskeletal inflammatory disease: evidence of arthritis, tenosynovitis, myositis, and persistence
    Thomas E Morrison
    Department of Microbiology, University of Colorado School of Medicine, Aurora, Colorado 80045, USA
    Am J Pathol 178:32-40. 2011
  10. pmc A protective role for complement C3 protein during pandemic 2009 H1N1 and H5N1 influenza A virus infection
    Kevin B O'Brien
    Department of Medical Microbiology and Immunology, University of Wisconsin, Madison, Wisconsin, United States of America
    PLoS ONE 6:e17377. 2011

Scientific Experts

  • Kristin M Rogers
  • Stacey Schultz-Cherry
  • Thomas E Morrison
  • Suresh Mahalingam
  • Mark T Heise
  • Bronwyn M Gunn
  • Amy C Wollish
  • Lance K Blevins
  • Alan C Whitmore
  • Lauren M Neighbours
  • Kevin B O'Brien
  • Henri J Jupille
  • Linda Hueston
  • Reed S Shabman
  • Michael Gale
  • Yueh Ming Loo
  • Martin T Ferris
  • Kristin Long
  • Lara J Herrero
  • Robert J Fraser
  • Paul N Smith
  • Ruben Ramirez
  • David Y Dundore
  • Kristina A Stoermer
  • Lauren Oko
  • Laura White
  • Mehul S Suthar
  • Jenny P Y Ting
  • Brett Lidbury
  • Nestor Rulli
  • Christopher Moore

Detail Information

Publications12

  1. pmc Characterization of Ross River virus tropism and virus-induced inflammation in a mouse model of viral arthritis and myositis
    Thomas E Morrison
    Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
    J Virol 80:737-49. 2006
    ..These results establish the mouse model of RRV disease as a useful system for the identification of viral and host factors that contribute to alphavirus-induced arthritis and myositis...
  2. pmc Myd88-dependent toll-like receptor 7 signaling mediates protection from severe Ross River virus-induced disease in mice
    Lauren M Neighbours
    Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
    J Virol 86:10675-85. 2012
    ..Additionally, TLR7- and Myd88-deficient mice showed defects in germinal center activity, suggesting that TLR7-dependent signaling is critical for the development of protective antibody responses against RRV...
  3. pmc An attenuating mutation in a neurovirulent Sindbis virus strain interacts with the IPS-1 signaling pathway in vivo
    Amy C Wollish
    Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA
    Virology 435:269-80. 2013
    ..These results indicate that the control of the nsP1 T538I mutant virus is largely mediated by IPS-1-dependent RLR signaling, with TRIF-dependent TLR signaling also contributing to protection from virus-induced neurologic disease...
  4. pmc Complement receptor 3 promotes severe ross river virus-induced disease
    Thomas E Morrison
    The Carolina Vaccine Institute, University of North Carolina at Chapel Hill, 9024 Burnett Womack, CB 7292, Manning Drive, Chapel Hill, NC 27599
    J Virol 82:11263-72. 2008
    ....
  5. ncbi The host complement system and arbovirus pathogenesis
    T E Morrison
    Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA
    Curr Drug Targets 9:165-72. 2008
    ..This review focuses on the increasing evidence that the complement system plays key roles in both protective and pathologic outcomes of arbovirus infection...
  6. pmc Complement contributes to inflammatory tissue destruction in a mouse model of Ross River virus-induced disease
    Thomas E Morrison
    Department of Genetics, University of North Carolina at Chapel Hill, NC 27599, USA
    J Virol 81:5132-43. 2007
    ....
  7. pmc Differential induction of type I interferon responses in myeloid dendritic cells by mosquito and mammalian-cell-derived alphaviruses
    Reed S Shabman
    Department of Genetics, The Carolina Vaccine Institute, The University of North Carolina, Chapel Hill, NC 27599, USA
    J Virol 81:237-47. 2007
    ..This difference may have an important impact on the mosquito-borne virus's ability to successfully make the transition from the arthropod vector to the vertebrate host...
  8. pmc Modulation of cellular tropism and innate antiviral response by viral glycans
    Kristin M Rogers
    Department of Genetics, Carolina Vaccine Institute, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
    J Innate Immun 1:405-12. 2009
    ..This review focuses on emerging evidence which supports a crucial role for viral glycans in mediating host cell tropism and regulating the innate antiviral response...
  9. pmc A mouse model of chikungunya virus-induced musculoskeletal inflammatory disease: evidence of arthritis, tenosynovitis, myositis, and persistence
    Thomas E Morrison
    Department of Microbiology, University of Colorado School of Medicine, Aurora, Colorado 80045, USA
    Am J Pathol 178:32-40. 2011
    ....
  10. pmc A protective role for complement C3 protein during pandemic 2009 H1N1 and H5N1 influenza A virus infection
    Kevin B O'Brien
    Department of Medical Microbiology and Immunology, University of Wisconsin, Madison, Wisconsin, United States of America
    PLoS ONE 6:e17377. 2011
    ..These studies suggest that although the levels of complement activation may differ depending on the influenza virus subtype, complement is an important host defense mechanism...
  11. pmc Mannose binding lectin is required for alphavirus-induced arthritis/myositis
    Bronwyn M Gunn
    Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America
    PLoS Pathog 8:e1002586. 2012
    ....
  12. pmc Mutations in nsP1 and PE2 are critical determinants of Ross River virus-induced musculoskeletal inflammatory disease in a mouse model
    Henri J Jupille
    Department of Microbiology, University of Colorado School of Medicine, Aurora, CO 80045, USA
    Virology 410:216-27. 2011
    ..These findings indicate that determinants in both nsP1 and PE2 have critical and distinct roles in the pathogenesis of RRV-induced musculoskeletal inflammatory disease in mice...