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Journal of Virology, June 2009, p. 5544-5555, Vol. 83, No. 11
0022-538X/09/$08.00+0     doi:10.1128/JVI.02673-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Major Histocompatibility Complex Haplotype Determines hsp70-Dependent Protection against Measles Virus Neurovirulence{triangledown}

Thomas Carsillo,1,2 Mary Carsillo,1,2 Zachary Traylor,1 Päivi Rajala-Schultz,3 Phillip Popovich,4 Stefan Niewiesk,1,2,4 and Michael Oglesbee1,4*

Department of Veterinary Biosciences,1 Center for Microbial Interface Biology,2 Department of Veterinary Preventive Medicine,3 Department of Molecular Virology, Immunology and Medical Genetics, the Ohio State University, Columbus, Ohio 432104

Received 29 December 2008/ Accepted 20 March 2009

In vitro studies show that hsp70 promotes gene expression for multiple viral families, although there are few reports on the in vivo significance of virus-hsp70 interaction. Previously we showed that hsp70-dependent stimulation of Edmonston measles virus (Ed MeV) transcription caused an increased cytopathic effect and mortality in transgenic hsp70-overexpressing C57BL/6 mice (H-2b). The response to MeV infection is influenced by the major histocompatibility complex haplotype; H-2d mice are resistant to brain infection due to robust antiviral immune responses, whereas H-2b mice are susceptible due to deficiencies in this response. We therefore tested the hypothesis that the outcome of MeV-hsp70 interaction may be dependent upon the host H-2 haplotype. The impact of selective neuronal hsp70 overexpression on Ed MeV brain infection was tested with congenic C57BL/10 H-2d neonatal mice. In this context, hsp70 overexpression conferred complete protection against virus-induced mortality, compared to >30% mortality in nontransgenic mice. Selective depletion of T-cell populations showed that transgenic mice exhibit a diminished reliance on T cells for protection. Brain transcript analysis indicated enhanced innate immune activation and signaling through Toll-like receptors 2 and 4 at early times postinfection for transgenic infected mice relative to those for nontransgenic infected mice. Collectively, results suggest that hsp70 can enhance innate antiviral immunity through Toll-like receptor signaling, supporting a protective role for physiological responses that enhance tissue levels of hsp70 (e.g., fever), and that the H-2 haplotype determines the effectiveness of this response.

* Corresponding author. Mailing address: Department of Veterinary Biosciences, The Ohio State University, 1925 Coffey Road, Columbus, OH 43210. Phone: (614) 292-9672. Fax: (614) 292-6473. E-mail: oglesbee.1{at}osu.edu

{triangledown} Published ahead of print on 25 March 2009.

Journal of Virology, June 2009, p. 5544-5555, Vol. 83, No. 11
0022-538X/09/$08.00+0     doi:10.1128/JVI.02673-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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