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Journal of Virology, November 2009, p. 11808-11818, Vol. 83, No. 22
0022-538X/09/$08.00+0     doi:10.1128/JVI.01346-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

The Roles of Chemokines in Rabies Virus Infection: Overexpression May Not Always Be Beneficial{triangledown}

Ling Zhao,1,2 Harufusa Toriumi,1,{dagger} Yi Kuang,1 Huanchun Chen,2 and Zhen F. Fu1,2,3*

Departments of Pathology,1 Infectious Diseases, College of Veterinary Medicine, University of Georgia, Athens, Georgia 30602,3 State-Key Laboratory of Agricultural Microbiology, Department of Preventive Veterinary, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, China2

Received 1 July 2009/ Accepted 31 August 2009

It was found previously that induction of innate immunity, particularly chemokines, is an important mechanism of rabies virus (RABV) attenuation. To evaluate the effect of overexpression of chemokines on RABV infection, chemokines macrophage inflammatory protein 1{alpha} (MIP-1{alpha}), RANTES, and IP-10 were individually cloned into the genome of attenuated RABV strain HEP-Flury. These recombinant RABVs were characterized in vitro for growth properties and expression of chemokines. It was found that all the recombinant viruses grew as well as the parent virus, and each of the viruses expressed the intended chemokine in a dose-dependent manner. When these viruses were evaluated for pathogenicity in the mouse model, it was found that overexpression of MIP-1{alpha} further decreased RABV pathogenicity by inducing a transient innate immune response. In contrast, overexpression of RANTES or IP-10 increased RABV pathogenicity by causing neurological diseases, which is due to persistent and high-level expression of chemokines, excessive infiltration and accumulation of inflammatory cells in the central nervous system, and severe enhancement of blood-brain barrier permeability. These studies indicate that overexpression of chemokines, although important in controlling virus infection, may not always be beneficial to the host.

* Corresponding author. Mailing address: Department of Pathology, College of Veterinary Medicine, University of Georgia, 501 D.W. Brooks Drive, Athens, GA 30602. Phone: (706) 542-7021. Fax: (706) 542-5828. E-mail: zhenfu{at}uga.edu

{triangledown} Published ahead of print on 9 September 2009.

{dagger} Present address: Research Institute for Production Development, 15, Shimogamo Morimoto-CHO, Sakyo-ku, 606-0805, Kyoto, Japan.

Journal of Virology, November 2009, p. 11808-11818, Vol. 83, No. 22
0022-538X/09/$08.00+0     doi:10.1128/JVI.01346-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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