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HSP70 AND A NOVEL AXIS OF TYPE I INTERFERON-DEPENDENT ANTIVIRAL IMMUNITY IN THE VIRUS-INFECTED BRAIN

Kim, Mi Young
http://rave.ohiolink.edu/etdc/view?acc_num=osu1374138000

Abstract Details

2013, Doctor of Philosophy, Ohio State University, Veterinary Biosciences.
The major inducible 70 kDa heat shock protein (hsp70) is host protective in a mouse model of measles virus (MeV) brain infection. Transgenic constitutive expression of hsp70 in neurons, the primary target of MeV infection, abrogates neurovirulence in neonatal H-2d congenic C57BL/6 mice. Focus of the present work was to elucidate the basis for hsp70-dependent innate immunity. Transcriptome analysis of brains from transgenic (TG) and non-transgenic (NT) mice identified type I interferon (IFN) signaling and macrophage activation/antigen presentation as the main differences linked to survival. The pivotal role for type I IFN in hsp70-mediated protection was demonstrated in mice with a genetically disrupted type I IFN receptor. In vitro studies provided a mechanistic basis by which MeV infected neurons can induce type I IFN in uninfected microglia in an hsp70-dependent manner. MeV infection induced extracellular release of hsp70 from mouse neuronal cells that constitutively express hsp70, and extracellular hsp70 induced IFN transcription in mouse microglial cells through Toll-like receptors 2 and 4. Vesicular stomatitis virus (VSV) was used to determine if the relevance of hsp70-dependent antiviral immunity extends to fulminant cytopathic neuronal infections. In vitro, VSV infection induced an early extracellular release of hsp70 from viable cells, similar to MeV. However, VSV-induced release was also progressive, increasing with virus-induced cell death. The impact of this VSV-hsp70 interaction on neurovirulence was also established in weanling male hsp70 TG and NT mice. Constitutive expression of hsp70 in neurons of TG mice enhanced viral clearance from brain and reduced mortality in a type I IFN-dependent manner. NT mice were also protected against neurovirulence in a type I dependent manner when hsp70 was expressed by a recombinant VSV (rVSV-hsp70), indicating that hsp70 expressed in the virus infected cell is sufficient for host protection. In vitro data confirmed extracellular release of hsp70 from cells infected with VSV-hsp70, and also showed that viral replication is not enhanced when hsp70 is expressed in this manner, suggesting that hsp70-mediated protection in vivo is not dependent on stimulatory effects of hsp70 on virus gene expression. In summary, my research has elucidated a role for hsp70 in enhancing type I IFN responses in the virus infected brain. In this model, hsp70 release from neurons serves as a sensor of virus infection, likely working in concert with other damage-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs)-mediated pathways to enhanced viral clearance. Results extend relevance of an hsp70-mediated axis of innate antiviral immunity from non-cytolytic MeV neuronal infection in neonates to include acute cytopathic infections mediated by VSV in weanling mice. These findings support a protective role of fever, a diagnostic feature of viral brain infection in humans and a potent inducer of hsp70. An hsp70-mediated host protective role for fever helps to explain why this physiological response to virus infection is highly conserved and how this novel axis of antiviral immunity can be exploited therapeutically. Moreover, these studies have led to research exploring the expression of hsp70 from recombinant live vaccines as a mean of enhancing vaccine efficacy and safety.
Michael Oglesbee (Advisor)
Stefan Niewiesk (Committee Member)
Prosper Boyaka (Committee Member)
Phillip Popovich (Committee Member)
Immunology; Virology

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Citations

  • Kim, M. Y. (2013). HSP70 AND A NOVEL AXIS OF TYPE I INTERFERON-DEPENDENT ANTIVIRAL IMMUNITY IN THE VIRUS-INFECTED BRAIN [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1374138000

    APA Style (7th edition)

  • Kim, Mi Young. HSP70 AND A NOVEL AXIS OF TYPE I INTERFERON-DEPENDENT ANTIVIRAL IMMUNITY IN THE VIRUS-INFECTED BRAIN. 2013. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1374138000.

    MLA Style (8th edition)

  • Kim, Mi Young. "HSP70 AND A NOVEL AXIS OF TYPE I INTERFERON-DEPENDENT ANTIVIRAL IMMUNITY IN THE VIRUS-INFECTED BRAIN." Doctoral dissertation, Ohio State University, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=osu1374138000

    Chicago Manual of Style (17th edition)

osu1374138000
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