Identifying chemokine receptors as plausible therapeutic targets in viral encephalitis

QR Microbiology;QR180 Immunology;QR355 Virology

Pajek, Daniela ; Graham, Gerard

University:University of Glasgow

Department:Institute of Infection Immunity and Inflammation

关键词: chemokines, alphavirus, Semliki Forest virus, viral encephalitis, small molecule antagonists, arbovirus, chemokine receptors, leukocyte infiltration into the CNS;   

Others  :  http://theses.gla.ac.uk/4764/1/2013PajekPhD.pdf

来源: University of Glasgow

【 摘 要 】

Background: There are a large number of viruses spread by mosquitoes, many of which cause debilitating, often fatal, neurological disease such as acute encephalitis. In this study we have used two different neurotropic viruses: Semliki Forest virus (SFV), and West Nile virus (WNV), both of which can cause severe panencephalitis in the mouse. The influx of leukocytes into the infected tissues is mediated by chemokines and is believed to be important for virus clearance. To date, we have only limited insights into the precise nature of chemokine involvement, and an improved understanding of these important axes provides a new target for the development of novel therapies. Hypothesis: Based on previous studies investigating the role of chemokines during neuroinflammation it was hypothesised that chemokines and other cytokines are highly upregulated during viral encephalitis, and the blockade of selected chemokine receptors would lead to altered disease outcome. It was also hypothesised that chemokine receptors would present plausible targets for the treatment of viral encephalitis. Results: To test these hypotheses, the chemokine expression pattern and the kinetics of chemokine mediated leukocyte recruitment during viral encephalitis were analysed in unprecedented detail by TaqMan low density array, and flow cytometry, respectively, and key chemokine receptor were identified as therapeutic targets. Both SFV and WNV exhibited a similar pattern of chemokine upregulation, although WNV induced significantly higher fold expression. The key chemokines upregulated were CCL2, 3, 5, 7, CXCL9 and CXCL10. The upregulation of chemokines coincided with leukocyte influx into the CNS. After identifying the key chemokines upregulated during viral encephalitis, next a selected panel of chemokine receptor antagonists was utilized to evaluate the hierarchy and relative importance of distinct chemokine receptors for CNS leukocyte influx, viral clearance, neuropathogenesis and host survival. We identified the CXCR3 axis as being the key instigator of CNS inflammation in response to alphavirus infection, placing it at the top of a hierarchal cascade that is followed by CCR2 and CCR5. Critically, inhibition of both CXCR3 and CCR2 simultaneously, significantly improved host survival to otherwise lethal encephalitis. Conclusion: These data suggest that chemokine receptors represent plausible therapeutic targets for viral encephalitis.