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A role for the major inducible 70 KDA heat shock protein (HSP72) in experimental measles encephalitis

Carsillo, Thomas John
http://rave.ohiolink.edu/etdc/view?acc_num=osu1141316578

Abstract Details

2006, Doctor of Philosophy, Ohio State University, Medical Microbiology and Immunology.
The cellular stress response is characterized by the expression of heat shock proteins (HSPs), and in particular hsp72. Elevated levels of hsp72 can mediate cellular stress conditioning, a state of heightened tolerance to noxious stimuli, where hsp72 persists into the post shock interval and allows cells to survive potential lethal injury. Paradoxically, increases in measles virus (MV) replication and gene expression are also seen in infected cells after induction of hsp72. The increase in MV transcription/replication has been attributed to a conserved motif on the MV nucleocapsid C-terminus, Box-3, where hsp72 can bind causing both structural and functional changes that increase transcription, replication, cytopathic effect and cell-free infectious progeny release. However, the outcome of MV-hsp72 interactions, in vivo, are completely unknown. The ability of hsp72 to increase viral gene expression may promote virulence. Conversely, HSPs have been shown to promote both innate and adaptive immune responses and may be host-protective. Using a Balb/c (H-2d) mouse model of MV-induced encephalitis we have demonstrated that heat shock (HS) increased viral clearance from brain where viral clearance is correlated to the onset of virus-specific cell mediated immune responses. Next, we ask if hsp72 expression alone can recapitulate the effects of HS. We generated a transgenic mouse (C57BL/6, H-2b) where hsp72 is overexpressed in neurons. Transgenic mice were highly susceptible to intracranial challenge with MV. In contrast, mice infected with Ed N-522D MV, a virus with an attenuated hsp72 responsiveness, showed no significant increase in mortality. The divergent outcomes are based on the mouse H-2 dependent ability to mount an effective antiviral immune response. These results suggest there would be selectional pressures on the virus to lose hsp72 responsiveness. N522D is a naturally occurring substitution frequently found in circulating wild type viruses and supports positive selection of this mutation. We establish fitness of a virus lacking hsp72 responsiveness and found that the N522D substitution diminishes fitness. Therefore, we hypothesize that immunological pressure is driving selection. Collectively, results presented here will be the first to show that hsp72 levels can directly influence the outcome of viral infection in an animal host.
Michael Oglesbee (Advisor)
156 p.
Biology, Molecular
Measles Virus; Hsp72; Neurovirulence

Recommended Citations

Citations

  • Carsillo, T. J. (2006). A role for the major inducible 70 KDA heat shock protein (HSP72) in experimental measles encephalitis [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1141316578

    APA Style (7th edition)

  • Carsillo, Thomas. A role for the major inducible 70 KDA heat shock protein (HSP72) in experimental measles encephalitis. 2006. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1141316578.

    MLA Style (8th edition)

  • Carsillo, Thomas. "A role for the major inducible 70 KDA heat shock protein (HSP72) in experimental measles encephalitis." Doctoral dissertation, Ohio State University, 2006. http://rave.ohiolink.edu/etdc/view?acc_num=osu1141316578

    Chicago Manual of Style (17th edition)

osu1141316578
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© 2006, all rights reserved.
This open access ETD is published by The Ohio State University and OhioLINK.