The major inducible heat shock protein (72 kDa HSP) increases canine distemper virus and measles virus (MV) nucleocapsid transcriptional activity, resulting in increased in vitro cytopathic effect. The first specific aim of this proposal will test the hypothesis that a 7 amino acid HSP binding motif on the exposed carboxyl terminus of the nucleocapsid (N) protein of MV mediates the functional interaction between kDa HSP and nucleocapsid (NC). The binding reaction between 72 kDa HSP and NC will be characterized for ribonucleoprotein complexes containing either intact N or N in which the carboxyl terminus has been removed by limited proteolysis. Synthetic peptides mimicking the motif will then be tested for their ability to (a) inhibit NC binding by HSP and (b) inhibit HSP-mediated stimulation of NC transcriptional activity. Finally, variations of this amino acid sequence mediating either high or low affinity HSP interaction will be incorporated into recombinant Edmondston-MV (Ed-MV) to directly test the role of this motif in mediating viral stress responsiveness and in vitro cytopathic effect. The second specific aim of this proposal will test the hypothesis that elevated expression of 72 kDa HSP in brain enhances neurovirulence of HV strains containing high-affinity HSP binding motifs whereas neurovirulence of strains containing low-affinity HSP binding motifs will be unaffected.
This specific aim will use available transgenic C57 mice that over-express 72 kDa HSP in neurons and recombinant infectious virus generated in specific aim one. Preliminary data show that intracranial inoculation of neonatal mice with Ed-MV causes a chronic persistent infection of brain in 65% of inoculated animals, such that enhanced viral gene expression mediated by elevated 72 kDa HSP should be manifest as increased lesion severity and/or the emergence of acute disease. Results of these studies can thus establish both viral and cellular determinants of neurovirulence and may lead to the development of novel approaches for treatment of viral encephalitis based upon inhibition of virus-HSP interaction.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Experimental Virology Study Section (EVR)
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Kerza-Kwiatecki, a P
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Ohio State University
Veterinary Sciences
Schools of Veterinary Medicine
United States
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Chawla, P; Cook, L; Himmell, L et al. (2015) Coextensive Meningioma and Cholesterol Granuloma in the Forebrain of a Cat. J Vet Intern Med 29:1638-42
Kim, Mi Young; Shu, Yaoling; Carsillo, Thomas et al. (2013) hsp70 and a novel axis of type I interferon-dependent antiviral immunity in the measles virus-infected brain. J Virol 87:998-1009
Moore, Sarah A; Kim, Mi Young; Maiolini, Arianna et al. (2012) Extracellular hsp70 release in canine Steroid Responsive Meningitis-Arteritis. Vet Immunol Immunopathol 145:129-33
Longhi, Sonia (2012) The measles virus N(TAIL)-XD complex: an illustrative example of fuzziness. Adv Exp Med Biol 725:126-41
Habchi, Johnny; Longhi, Sonia (2012) Structural disorder within paramyxovirus nucleoproteins and phosphoproteins. Mol Biosyst 8:69-81
Shu, Yaoling; Habchi, Johnny; Costanzo, St├ęphanie et al. (2012) Plasticity in structural and functional interactions between the phosphoprotein and nucleoprotein of measles virus. J Biol Chem 287:11951-67
Halgand, F; Habchi, Johnny; Cravello, Laetitia et al. (2011) Dividing to unveil protein microheterogeneities: traveling wave ion mobility study. Anal Chem 83:7306-15
Oglesbee, Michael; Niewiesk, Stefan (2011) Measles virus neurovirulence and host immunity. Future Virol 6:85-99
Gely, Stephane; Lowry, David F; Bernard, Cedric et al. (2010) Solution structure of the C-terminal X domain of the measles virus phosphoprotein and interaction with the intrinsically disordered C-terminal domain of the nucleoprotein. J Mol Recognit 23:435-47
Couturier, Marie; Buccellato, Matt; Costanzo, Stephanie et al. (2010) High affinity binding between Hsp70 and the C-terminal domain of the measles virus nucleoprotein requires an Hsp40 co-chaperone. J Mol Recognit 23:301-15

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