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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Available from: Yi Kuang, Oct 06, 2015
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    • "It should be noted that although overexpression of cytokines/chemokines has important roles in controlling virus infection and RABV attenuation, certain cytokines/ chemokines, such as RANTES or IP-10, when overexpressed, are detrimental (Zhao et al. 2009). It has been shown that when RANTES or IP-10 was overexpressed, the RABV pathogenicity in mice was increased owing to persistent and highlevel expression of chemokines, extensive infiltration of inflammatory cells in the CNS, and severe enhancement of BBB permeability (Zhao et al. 2009). Therefore, much work should be performed in the future to comprehensively investigate the physiological effect of cytokines/ chemokine expression before RABVs overexpressing cytokines/chemokines are to be developed to treat clinical rabies or other CNS diseases due to the complex responses triggered by cytokines/chemokines. "
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    ABSTRACT: Rabies is an ancient neurological disease that is almost invariably fatal once the clinical symptoms develop. Currently, prompt wound cleansing after exposing to a potentially rabid animal and vaccination using rabies vaccine combined with administration of rabies immune globulin are the only effective methods for post-exposure prophylaxis against rabies. Reverse genetic technique is a novel approach to investigate the function of a specific gene by analyzing the phenotypic effects through directly manipulating the gene sequences. It has revolutionized and provided a powerful tool to study the molecular biology of RNA viruses and has been widely used in rabies virus research. The attenuation of rabies virus virulence is the prerequisite for rabies vaccine development. Given the current challenge that sufficient and affordable high-quality vaccines are limited and lacking for global rabies prevention and control, highly cell-adapted, stable, and attenuated rabies viruses with broad cross-reactivity against different viral variants are ideal candidates for consideration to meet the need for human rabies control in the future. A number of approaches have been pursued to reduce the virulence of the virus and improve the safety of rabies vaccines. The application of reverse genetic technique has greatly advanced the engineering of rabies virus and paves the avenue for utilizing rabies virus for vaccine against rabies, viral vectors for exogenous antigen expression, and gene therapy in the future.
    Journal of NeuroVirology 05/2015; 21(4). DOI:10.1007/s13365-015-0350-2 · 2.60 Impact Factor
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    • "Samples of culture medium were harvested at 12, 24, 48, 72 h post-inoculation (p.i.). Virus titer was determined in NA cells by the dFA as described (Zhao et al., 2009). Fig. 1. "
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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.
    Veterinary Microbiology 11/2012; 162(2-4). DOI:10.1016/j.vetmic.2012.11.031 · 2.51 Impact Factor
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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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    ABSTRACT: Background Rabies virus (RABV) causes a fatal infection of the central nervous systems (CNS) of warm-blooded animals. Once the clinical symptoms develop, rabies is almost invariably fatal. The mechanism of RABV pathogenesis remains poorly understood. Recent studies have shown that microRNA (miRNA) plays an important role in the pathogenesis of viral infections. Our recent findings have revealed that infection with laboratory-fixed rabies virus strain can induce modulation of the microRNA profile of mouse brains. However, no previous report has evaluated the miRNA expression profile of mouse brains infected with RABV street strain. Results The results of microarray analysis show that miRNA expression becomes modulated in the brains of mice infected with street RABV. Quantitative real-time PCR assay of the differentially expressed miRNAs confirmed the results of microarray assay. Functional analysis showed the differentially expressed miRNAs to be involved in many immune-related signaling pathways, such as the Jak-STAT signaling pathway, the MAPK signaling pathway, cytokine-cytokine receptor interactions, and Fc gamma R-mediated phagocytosis. The predicted expression levels of the target genes of these modulated miRNAs were found to be correlated with gene expression as measured by DNA microarray and qRT-PCR. Conclusion RABV causes significant changes in the miRNA expression profiles of infected mouse brains. Predicted target genes of the differentially expression miRNAs are associated with host immune response, which may provide important information for investigation of RABV pathogenesis and therapeutic method.
    Virology Journal 08/2012; 9(1):159. DOI:10.1186/1743-422X-9-159 · 2.18 Impact Factor
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