Small Interfering RNA Targeting the Nonstructural Gene 1 Transcript Inhibits Influenza A Virus Replication in Experimental Mice

Rajput, Roopali; Khanna, Madhu; Kumar, Pankaj; Kumar, Binod; Sharma, Sonal; Gupta, Neha; Saxena, Latika

doi:10.1089/nat.2012.0359

Cited by 25 publications

(14 citation statements)

References 44 publications

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“…Other factors that may explain differential duck and chicken responses to influenza include viral modification of the immune system such as by influenza NS1 which blocks key cellular protective mechanisms (Rajput et al, 2012). In particular, NS1 interacts with the RIG-like helicases further suggesting the importance of RIG-I for protecting influenza-infected organisms (Rückle et al, 2012).…”

Section: Figmentioning

confidence: 99%

H5N1 infection causes rapid mortality and high cytokine levels in chickens compared to ducks

et al. 2014

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Infection with H5N1 influenza virus is often fatal to poultry with death occurring in hours rather than days. However, whilst chickens may be acutely susceptible, ducks appear to be asymptomatic to H5N1. The mechanisms of disease pathogenesis are not well understood and the variation between different species requires investigation to help explain these species differences. Here we investigated the expression of several key proinflammatory cytokines of chickens and ducks following infection with 2 highly pathogenic H5N1 (A/Muscovy duck/Vietnam/453/2004 (Vt453) and A/Duck/Indramayu/BBVW/109/2006 (Ind109)) and a low-pathogenic H5N3 influenza virus (A/Duck/Victoria/1462/2008 (Vc1462)). H5N1 viruses caused fatal infections in chickens as well as high viral loads and increased production of proinflammatory molecules when compared to ducks. Cytokines, including Interleukin 6 (IL6) and the acute phase protein Serum Amyloid A (SAA), were rapidly induced at 24h post infection with H5N1. In contrast, low induction of these cytokines appeared in ducks and only at later times during the infection period. These observations support that hypercytokinemia may contribute to pathogenesis in chickens, whilst the lower cytokine response in ducks may be a factor in their apparent resistance to disease and decreased mortality.

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Section: Figmentioning

confidence: 99%

H5N1 infection causes rapid mortality and high cytokine levels in chickens compared to ducks

et al. 2014

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“…Rajput et al observed a 60% inhibition of NS1 RNA with either of two NS1-specific siRNAs in co-transfection experiments using an NS1 expression construct in MDCK cells (Rajput et al, 2012). Remarkably, intravenous administration of increasing doses of NS1-specific siRNA in BALB/c mice challenged with 2×10 6 p.f.u.…”

Section: Nucleic Acid-based Ns1 Inhibitorsmentioning

confidence: 99%

The influenza virus NS1 protein as a therapeutic target

Engel

2013

Antiviral Research

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Nonstructural protein 1 (NS1) of influenza A virus plays a central role in virus replication and blockade of the host innate immune response, and is therefore being considered as a potential therapeutic target. The primary function of NS1 is to dampen the host interferon (IFN) response through several distinct molecular mechanisms that are triggered by interactions with dsRNA or specific cellular proteins. Sequestration of dsRNA by NS1 results in inhibition of the 2’-5’ oligoadenylate synthetase/RNase L antiviral pathway, and also inhibition of dsRNA-dependent signaling required for new IFN production. Binding of NS1 to the E3 ubiquitin ligase TRIM25 prevents activation of RIG-I signaling and subsequent IFN induction. Cellular RNA processing is also targeted by NS1, through recognition of cleavage and polyadenylation specificity factor 30 (CPSF30), leading to inhibition of IFN- mRNA processing as well as that of other cellular mRNAs. In addition NS1 binds to and inhibits cellular protein kinase R (PKR), thus blocking an important arm of the IFN system. Many additional proteins have been reported to interact with NS1, either directly or indirectly, which may serve its anti-IFN and additional functions, including the regulation of viral and host gene expression, signaling pathways and viral pathogenesis. Many of these interactions are potential targets for small-molecule intervention. Structural, biochemical and functional studies have resulted in hypotheses for drug discovery approaches that are beginning to bear experimental fruit, such as targeting the dsRNA-NS1 interaction, which could lead to restoration of innate immune function and inhibition of virus replication. This review describes biochemical, cell-based and nucleic acid-based approaches to identifying NS1 antagonists.

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“…88 Furthermore, Rajput et al reported that when NS1-specific siRNA was administered in experimental mice, a 92% reduction was observed in the levels of NS1 gene expression in the lungs. 98 Significant decrease in cytokine levels and virus titers in the lungs were also observed. Zhou et al also designed three siRNAs against the NP, PB1 and PA proteins of H5N1 avian influenza virus.…”

Section: Possibility Of Use As Anti-influenza Agent In Human and Animalsmentioning

confidence: 87%

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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Small Interfering RNA Targeting the Nonstructural Gene 1 Transcript Inhibits Influenza A Virus Replication in Experimental Mice

Cited by 25 publications

References 44 publications

H5N1 infection causes rapid mortality and high cytokine levels in chickens compared to ducks

H5N1 infection causes rapid mortality and high cytokine levels in chickens compared to ducks

The influenza virus NS1 protein as a therapeutic target

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

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