Control of alphavirous replacation in the nervous system

Summary

Principal Investigator: Diane E Griffin
Abstract: DESCRIPTION (provided by applicant): Arthropod-borne (arbo) viruses, most importantly alphaviruses and flaviviruses, cause widespread epidemics of fever, encephalitis and arthritis and pose increasing threats to human populations through expansion into new geographic areas. Encephalomyelitis due to arbovirus infection of neurons is a particularly important global cause of morbidity and mortality because neuronal damage can lead to chronic disease and long-term disability, as well as acute fatal disease. There are no treatments for these infections and vaccines are not available for most. Alphaviruses that cause encephalitis (Venezuelan, western and eastern equine encephalitis viruses) infect neurons and are endemic in the Americas. Recovery from infection requires virus clearance from neurons and this poses unique challenges for the immune system. A noncytolytic process is needed to avoid irreversible neurologic damage and the process must be effective to avoid chronic or progressive neurologic disease. Our studies of the prototype alphavirus, Sindbis virus (SINV), in mice have shown that neurons are the primary target cells and that both virus and host factors determine outcome. Strains that cause acute nonfatal encephalomyelitis in weanling mice (e.g. AR339, TE) provide a system for studying the complicated process of recovery from neuronal virus infection. We have shown that infectious virus can be cleared by the combined effects of antibody (Ab) to the SINV E2 glycoprotein and interferon (IFN)-g, through processes that do not damage the infected neurons. However, preservation of these essential cells results in persistence of viral RNA in the central nervous system (CNS) and the need for long-term suppression of virus replication. Detailed study of virus clearance from the CNS of immunologically normal 4-6 week-old C57BL/6 mice over 6 months has revealed 3 phases of the clearance process: 1) clearance of infectious virus, but continued high levels of viral RNA;2) gradual decrease in the amounts of viral RNA without production of infectious virus;and 3) maintenance of viral RNA at low levels with prevention of virus reactivation. We hypothesize that different components of the immune response are essential for each of these stages. We will define the mechanisms of staged recovery from SINV encephalomyelitis through the following specific aims: (1) Determine the components of the immune response that clear infectious virus from the CNS;(2) Determine the components of the immune response that decrease viral RNA in the CNS after infectious virus is cleared;and (3) Determine the role and maintenance of resident antibody-secreting cells in inhibition of virus reactivation.
Funding Period: 2001-07-01 - 2016-11-30
more information: NIH RePORT

Top Publications

  1. pmc Noncytolytic clearance of sindbis virus infection from neurons by gamma interferon is dependent on Jak/STAT signaling
    Rebeca Burdeinick-Kerr
    W Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, 615 North Wolfe Street, Baltimore, MD 21205, USA
    J Virol 83:3429-35. 2009
  2. pmc Recovery from viral encephalomyelitis: immune-mediated noncytolytic virus clearance from neurons
    Diane E Griffin
    W Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Rm E5132, Baltimore, MD 21205, USA
    Immunol Res 47:123-33. 2010
  3. pmc Alphavirus-induced encephalomyelitis: antibody-secreting cells and viral clearance from the nervous system
    Talibah U Metcalf
    Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, 615 North Wolfe Street, Baltimore, MD 21205, USA
    J Virol 85:11490-501. 2011
  4. pmc Clearance of virus infection from the CNS
    Diane E Griffin
    Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg, School of Public Health, Baltimore, MD 21205, USA
    Curr Opin Virol 1:216-21. 2011
  5. pmc Recruitment and retention of B cells in the central nervous system in response to alphavirus encephalomyelitis
    Talibah U Metcalf
    W Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland, USA
    J Virol 87:2420-9. 2013
  6. pmc Functional characterization of the alphavirus TF protein
    Jonathan E Snyder
    Markey Center for Structural Biology, Department of Biological Sciences, Purdue University, West Lafayette, Indiana, USA
    J Virol 87:8511-23. 2013
  7. pmc Mice deficient in interferon-gamma or interferon-gamma receptor 1 have distinct inflammatory responses to acute viral encephalomyelitis
    Eun Young Lee
    W Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, United States of America
    PLoS ONE 8:e76412. 2013
  8. pmc Replication of many human viruses is refractory to inhibition by endogenous cellular microRNAs
    Hal P Bogerd
    Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina, USA
    J Virol 88:8065-76. 2014

Detail Information

Publications9

  1. pmc Noncytolytic clearance of sindbis virus infection from neurons by gamma interferon is dependent on Jak/STAT signaling
    Rebeca Burdeinick-Kerr
    W Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, 615 North Wolfe Street, Baltimore, MD 21205, USA
    J Virol 83:3429-35. 2009
    ..We conclude that activation of the Jak/Stat pathway is the primary mechanism for IFN-gamma-mediated clearance of SINV infection from mature neurons...
  2. pmc Recovery from viral encephalomyelitis: immune-mediated noncytolytic virus clearance from neurons
    Diane E Griffin
    W Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Rm E5132, Baltimore, MD 21205, USA
    Immunol Res 47:123-33. 2010
    ..Virus-specific antibody-secreting cells residing in the nervous system after recovery from infection are likely to be important for long-term control...
  3. pmc Alphavirus-induced encephalomyelitis: antibody-secreting cells and viral clearance from the nervous system
    Talibah U Metcalf
    Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, 615 North Wolfe Street, Baltimore, MD 21205, USA
    J Virol 85:11490-501. 2011
    ..However, there was no evidence of germinal center activity or IgG avidity maturation within the CNS...
  4. pmc Clearance of virus infection from the CNS
    Diane E Griffin
    Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg, School of Public Health, Baltimore, MD 21205, USA
    Curr Opin Virol 1:216-21. 2011
    ..Antiviral antibody and interferon-γ have major roles in clearance with a likely role for IgM as well as IgG antibody. Long-term residence of virus-specific immune cells in the nervous system is necessary to prevent virus reactivation...
  5. pmc Recruitment and retention of B cells in the central nervous system in response to alphavirus encephalomyelitis
    Talibah U Metcalf
    W Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland, USA
    J Virol 87:2420-9. 2013
    ..We conclude that multiple changes in the brain microenvironment facilitate B-cell entry and support proliferation and differentiation and long-term survival of antiviral ASCs during recovery from alphaviral encephalomyelitis...
  6. pmc Functional characterization of the alphavirus TF protein
    Jonathan E Snyder
    Markey Center for Structural Biology, Department of Biological Sciences, Purdue University, West Lafayette, Indiana, USA
    J Virol 87:8511-23. 2013
    ..The TF protein therefore represents a previously uncharacterized factor important for alphavirus assembly. ..
  7. pmc Mice deficient in interferon-gamma or interferon-gamma receptor 1 have distinct inflammatory responses to acute viral encephalomyelitis
    Eun Young Lee
    W Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, United States of America
    PLoS ONE 8:e76412. 2013
    ..Therefore, GKO and GRKO cannot be considered equivalent when assessing the role of IFN-gamma in CNS viral infections. ..
  8. pmc Replication of many human viruses is refractory to inhibition by endogenous cellular microRNAs
    Hal P Bogerd
    Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina, USA
    J Virol 88:8065-76. 2014
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