Inhibition of highly pathogenic avian H5N1 influenza virus propagation by RNA oligonucleotides targeting the PB2 gene in combination with celecoxib

Abstract

Highly pathogenic avian influenza virus H5N1 can cause acute respiratory infections with an uncontrolled virus-induced cytokine storm in both poultry and humans. In view of the high mortality of H5N1 influenza virus infection, the development of novel broad-spectrum prophylactic and therapeutic agents against infection is urgently needed. In the present study, we attempted to explore whether the combinational use of a viral gene-targeted agent and immunomodulator is feasible as a new strategy against the H5N1 infection. Four antisense RNA oligonucleotides targeting the polymerase basic protein 2 (PB2) gene of H5N1-HPIV were designed and screened for their ability to inhibit H5N1 influenza viral propagation. In Madin-Darby canine kidney cells, the RNA oligonucleotides efficiently inhibited viral replication, as measured by hemagglutinin production, plaque formation and viral RNA expression assays. In a mouse infection model, a combinational treatment in mice with the PB2 oligonucleotides and celecoxib significantly reduced the viral load, regulated cytokine profiles, and improved lung lesions and animal survival compared to the single use of either PB2 oligonucleotides or the immunomodulatory agent, celecoxib. The results obtained in the present study suggest the potential use of PB2-targeted oligonucleotides in conjunction with immunomodulators for the control of H5N1 influenza infection.