Platelet Factor 4 Promotes Rapid Replication and Propagation of Dengue and Japanese Encephalitis Viruses

In order to investigate the mechanism of rapid propagation of closely related Dengue virus (DV) and Japanese encephalitis virus (JEV) in host, our study describes the direct association of the host protein, platelet factor 4 (PF4) in enhancing significantly the replication and propagation of DV in monocytes in vitro and in patients. Blocking PF4 in vitro through antibodies or its receptor CXCR3 through inhibitor i.e. AMG487, significantly rescued production of anti-viral cytokines including interferon (IFN)-α resulting in potent inhibition of DV replication in monocytes in vitro. Similarly, PF4 also showed direct effects in promoting the JEV replication in monocytes and microglia cells in vitro. The in vitro results were also validated in mice, where blocking CXCR3 with AMG487 treatment significantly decreased JEV infection while enhancing survival of infected animals. Therefore, our study suggests that PF4-CXCR3-IFN axis is a potential target for developing treatment regimen against viral infections including JEV and DV. Funding: This study was financially supported by grants: BT/PR8591 from the Department of Biotechnology, Govt. of India to Prasenjit Guchhait and Tulika Seth; BT/PR22985 from the Department of Biotechnology, Govt. of India to Prasenjit Guchhait, Sankar Bhattacharyya and Naval K. Vikram; Tata Innovation Fellowship BT/HRD/35/01/02/2014 from the Department of Biotechnology, Govt. of India to Anirban Basu (NBRC). Declaration of Interest: Authors do not have any financial or other disclosures. Ethical Approval: The animal study protocol was approved and the experiments were carried out as per the guidelines of the Institutional Animal Ethics Committee. The ethics approval was obtained from the Institutional Human Ethics Committee of Regional Centre for Biotechnology for the collection of peripheral blood from patients and healthy volunteers.