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

Department of Pathology, College of Veterinary Medicine, University of Georgia, Athens, GA 30602, USA.
Journal of Virology (Impact Factor: 4.44). 10/2009; 83(22):11808-18. DOI: 10.1128/JVI.01346-09
Source: PubMed


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 1α (MIP-1α), 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-1α
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.

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    ABSTRACT: Our previous studies have suggested that street and fixed rabies viruses (RABVs) induce diseases in the mouse model via different mechanisms. In the present study, attempts were made to determine if it is the glycoprotein (G) that is responsible for the observed differences in the pathogenic mechanisms. To this end, an infectious clone from fixed virus B2c was established and used as a backbone for exchange of the G from street viruses. The rate of viral replication, expression of viral proteins, and the induction of innate immune responses were compared in cells or in mice infected with each of the viruses. Furthermore, the infiltration of inflammatory cells into the CNS and the enhancement of blood-brain barrier (BBB) permeability were also compared. It was found that fixed viruses induced stronger innate immune responses (expression of chemokines, infiltration of inflammatory cells, and enhancement of BBB permeability) than street RABV or recombinant viruses expressing the G from street RABVs. Fixed viruses induce disease via an immune-mediated pathogenic mechanism while street viruses or recombinant viruses expressing the G from street RABVs induce diseases via a mechanism other than immune-mediated pathogenesis. Therefore, RABV G is an important determinant for the induction of innate immune responses and consequently the pathogenic mechanisms.
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    • "Recent studies have revealed the important regulatory roles played by cytokines and their receptors in RABV infection. One study showed that over-expression of cytokine CCL3 (MIP-1α) in mouse brains decreased RABV pathogenicity [41]. The same research team also demonstrated that MIP-1α not only reduces viral pathogenicity but also enhances immunogenicity by recruiting dendritic cells and B cells to the sites of immunization, lymph nodes, and blood [42]. "
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