siRNAs targeting PB2 and NP genes potentially inhibit replication of Highly Pathogenic H5N1 Avian Influenza Virus

Behera, P.; Nagarajan, S.; Murugkar, H. V.; Kalaiyarasu, Semmannan; Prakash, Anil; Gothalwal, Ragini; Dubey, Sonali; Kulkarni, D. D.; Tosh, C.

doi:10.1007/s12038-015-9524-6

Cited by 9 publications

(7 citation statements)

References 41 publications

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“…Different types of RNAs are expressed in virus-infected cells during an IAV life cycle, including mRNA, viral genomic RNA (vRNA), and complementary RNA (cRNA), all of which can be potential targets for degradation mediated by siRNAs. Various types of siRNAs have been reported to be effective in inhibiting the replication of IAV, including siRNAs specific for PB2, PB1, PA, NP, M1, M2, and NS1 viral genes (25,37,39,(45)(46)(47)(48)(49). However, most of the studies have been based on chemically synthesized single-site siRNAs.…”

Section: Discussionmentioning

confidence: 99%

Efficient Inhibition of Avian and Seasonal Influenza A Viruses by a Virus-Specific Dicer-Substrate Small Interfering RNA Swarm in Human Monocyte-Derived Macrophages and Dendritic Cells

Jiang

Österlund

Westenius

et al. 2019

J Virol

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Influenza A viruses (IAVs) are viral pathogens that cause epidemics and occasional pandemics of significant mortality. The generation of efficacious vaccines and antiviral drugs remains a challenge due to the rapid appearance of new influenza virus types and antigenic variants. Consequently, novel strategies for the prevention and treatment of IAV infections are needed, given the limitations of the presently available antivirals. Here, we used enzymatically produced IAV-specific double-stranded RNA (dsRNA) molecules and Giardia intestinalis Dicer for the generation of a swarm of small interfering RNA (siRNA) molecules. The siRNAs target multiple conserved genomic regions of the IAVs. In mammalian cells, the produced 25-to 27-nucleotide-long siRNA molecules are processed by endogenous Dicer into 21-nucleotide siRNAs and are thus designated Dicer-substrate siRNAs (DsiRNAs). We evaluated the efficacy of the above DsiRNA swarm at preventing IAV infections in human primary monocyte-derived macrophages and dendritic cells. The replication of different IAV strains, including avian influenza H5N1 and H7N9 viruses, was significantly inhibited by pretransfection of the cells with the IAV-specific DsiRNA swarm. Up to 7 orders of magnitude inhibition of viral RNA expression was observed, which led to a dramatic inhibition of IAV protein synthesis and virus production. The IAV-specific DsiRNA swarm inhibited virus replication directly through the RNA interference pathway although a weak induction of innate interferon responses was detected. Our results provide direct evidence for the feasibility of the siRNA strategy and the potency of DsiRNA swarms in the prevention and treatment of influenza, including the highly pathogenic avian influenza viruses. IMPORTANCE In spite of the enormous amount of research, influenza virus is still one of the major challenges for medical virology due to its capacity to generate new variants, which potentially lead to severe epidemics and pandemics. We demonstrated here that a swarm of small interfering RNA (siRNA) molecules, including more than 100 different antiviral RNA molecules targeting the most conserved regions of the influenza A virus genome, could efficiently inhibit the replication of all tested avian and seasonal influenza A variants in human primary monocyte-derived macrophages and dendritic cells. The wide antiviral spectrum makes the virusspecific siRNA swarm a potentially efficient treatment modality against both avian and seasonal influenza viruses. KEYWORDSDicer-substrate siRNA, DsiRNA, RNA interference, avian influenza virus, gene silencing, human macrophage, human moDC, influenza A virus, IAV, interferon response, IFN, siRNA swarm, viral replication Citation Jiang M, Österlund P, Westenius V, Guo D, Poranen MM, Bamford DH, Julkunen I. 2019. Efficient inhibition of avian and seasonal influenza A viruses by a virus-specific Dicersubstrate small interfering RNA swarm in human monocyte-derived macrophages and dendritic cells. J Virol 93:e01916-18. https://doi .

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Section: Discussionmentioning

confidence: 99%

Efficient Inhibition of Avian and Seasonal Influenza A Viruses by a Virus-Specific Dicer-Substrate Small Interfering RNA Swarm in Human Monocyte-Derived Macrophages and Dendritic Cells

Jiang

Österlund

Westenius

et al. 2019

J Virol

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“…In a recent report, Behera and co-workers observed, using three siRNAs designed against the PB2 and NP gene segments of HPAI H5N1 (identified as PB2-2235, PB2-479 and NP-865), 8-to 16-fold reduction in virus HA titers, 68-80% reduction in viral plaque counts, and 87-94% reduction in RNA copy number for 48 hours (maximum observation period) after challenge with 100TCID50 of virus. 94 Sui et al also reported that inhibition of propagation of H1N1 and HPAI H5N1 viruses in stable cell lines by siRNAs targeting the M2 gene was sustained for more than 50 hours post-infection. 79 Similar results were obtained by Ge et al in MDCK cells using siRNA targeting the NP gene (NP-1496).…”

Section: Broad Anti-influenza Spectrum and Long-term Inhibitory Effectmentioning

confidence: 99%

Treatment of Influenza: Prospects of Post-Transcriptional Gene Silencing Through Synthetic siRNAs

Adeola¹

2017

Exploratory Research and Hypothesis in Medicine

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Influenza continues to pose significant threats to global health. The disease remains life-threatening, especially in children, the elderly and immunocompromised patients. High mutation rate and genetic reassortment enhance antigenic diversity and generation of novel strains. These, and other related factors, have made influenza viruses more resistant to control strategies and have necessitated the need for development of novel and effective strategies for prevention and treatment of influenza. While vaccination is the preferred method for prevention of influenza virus infections, preparation of influenza vaccines has to be carried out annually, and this takes several months. Anti-influenza drugs would, therefore, be the most immediate resource for combating newly emerging influenza viruses, especially if available vaccines proved ineffective. This review discusses the prospects of using small interfering RNAs (siRNAs) for treatment of influenza. Challenges associated with anti-influenza RNA interference (RNAi) and future directions are also highlighted

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“…Moreover, coupling siRNAs with various pro-cell carriers to form small molecules can increase the permeability of cells and reduce innate immunity responses [27,31]. In addition, when siRNA is applied to the stem-loop structure of mRNA, the siRNA inhibition rate can be increased [34]. The siRNA designed for M and NS transcripts with primary transcripts exhibited enhanced silencing effect [19].…”

Section: Problems and Prospects Of Sirna In Anti-influenza Viral Infementioning

confidence: 99%

Research progress of siRNA in anti-influenza viral infection

Han¹

2018

Infection International

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The harms of seasonal flu and global pandemic influenza have generally attracted attention. However, the currently administered influenza drugs and flu vaccines have certain limitations. Since the discovery of the small interfering RNA (siRNA) and its mediated RNA interference process, this molecule has been widely used in the study of anti-influenza viral infections because of its high specificity and strong selectivity. The results provided new concepts for the prevention and treatment of influenza virus. However, the siRNA still faces an enormous challenge despite extensive studies on this molecule. The research progress of siRNA in anti-influenza viral infection was reviewed in this study.

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siRNAs targeting PB2 and NP genes potentially inhibit replication of Highly Pathogenic H5N1 Avian Influenza Virus

Cited by 9 publications

References 41 publications

Efficient Inhibition of Avian and Seasonal Influenza A Viruses by a Virus-Specific Dicer-Substrate Small Interfering RNA Swarm in Human Monocyte-Derived Macrophages and Dendritic Cells

Efficient Inhibition of Avian and Seasonal Influenza A Viruses by a Virus-Specific Dicer-Substrate Small Interfering RNA Swarm in Human Monocyte-Derived Macrophages and Dendritic Cells

Treatment of Influenza: Prospects of Post-Transcriptional Gene Silencing Through Synthetic siRNAs

Research progress of siRNA in anti-influenza viral infection

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