Abstract
Influenza A virus infections are important causes of morbidity and mortality worldwide, and currently available prevention and treatment methods are suboptimal. In recent years, genome-wide investigations have revealed numerous host factors that are required for influenza to successfully complete its life cycle. However, only a select, small number of influenza strains were evaluated using this platform, and there was considerable variation in the genes identified across different investigations. In an effort to develop a universally efficacious therapeutic strategy with limited potential for the emergence of resistance, this study was performed to investigate the effect of combinatorial RNA interference (RNAi) on inhibiting the replication of diverse influenza A virus subtypes and strains. Candidate genes were selected for targeting based on the results of multiple previous independent genome-wide studies. The effect of single and combinatorial RNAi on the replication of 12 diverse influenza A viruses, including three strains isolated from birds and one strain isolated from seals, was then evaluated in primary normal human bronchial epithelial cells. After excluding overly toxic siRNA, two siRNA combinations were identified that reduced mean viral replication by greater than 79 percent in all mammalian strains, and greater than 68 percent in all avian strains. Host-directed combinatorial RNAi effectively prevents growth of a broad range of influenza virus strains in vitro, and is a potential therapeutic candidate for further development and future in vivo studies.
Highlights
Influenza A viruses (IAVs) are members of the Orthomyxoviridae family possessing negativestranded segmented RNA genomes [1]
Seven representative genes among the 33 identified targets were selected as putative candidates for single and combinatorial RNA interference (RNAi) experiments
The PRPF8 gene, which is involved in the splicing machinery, was reported by three independent publications as important for influenza virus replication, it was not included in our study due to the likely cytotoxic effect of its knockdown as demonstrated in prior studies [55,56,57]
Summary
Influenza A viruses (IAVs) are members of the Orthomyxoviridae family possessing negativestranded segmented RNA genomes [1]. Wild birds are the natural reservoirs of IAVs, where they establish mainly asymptomatic infections. By virtue of their segmented genome and error. Host-directed combinatorial RNAi improves inhibition of influenza virus study design, data collection and analysis, decision to publish, or preparation of the manuscript
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