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Co-immunoprecipitation of the Mouse Mx1 Protein with the Influenza A Virus Nucleoprotein
Published on: April 21, 2015
MicroRNA-206 inhibits influenza A virus replication by targeting tankyrase 2
Gayan Bamunuarachchi1,2, Xiaoyun Yang1,2, Chaoqun Huang1,2
1Oklahoma Center for Respiratory and Infectious Diseases, Oklahoma State University, Stillwater, Oklahoma, USA.
Abstract:
Due to the frequent mutations, influenza A virus (IAV) becomes resistant to anti-viral drugs targeting influenza viral proteins. There are increasing interests in anti-viral agents that target host cellular proteins required for virus replication. Tankyrase (TNKS) has poly (ADP-ribose) polymerase activity and is a negative regulator of many host proteins. The objectives of this study are to study the role of TNKS2 in IAV infection, identify the microRNAs targeting TNKS2, and to understand the mechanisms involved. We found that TNKS2 expression was elevated in human lung epithelial cells and mouse lungs during IAV infection. Knock-down of TNKS2 by RNA interference reduced viral replication. Using a computation approach and 3'-untranslation regions (3'-UTR) reporter assay, we identified miR-206 as the microRNA that targeted TNKS2. Overexpression of miR-206 reduced viral protein levels and virus production in cell culture. The effect of miR-206 on IAV replication was strain-independent. miR-206 activated JNK/c-Jun signalling, induced type I interferon expression and enhanced Stat signalling. Finally, the delivery of an adenovirus expressing miR-206 into the lung of mice challenged with IAV increased type I interferon response, suppressed viral load in the lungs and increased survival. Our results indicate that miR-206 has anti-influenza activity by targeting TNKS2 and subsequently activating the anti-viral state.
Insights
New research reveals that miR-206 combats influenza A virus (IAV) by targeting the host protein Tankyrase 2 (TNKS2). This microRNA enhances the anti-viral state, offering a novel therapeutic strategy against drug-resistant influenza strains.
Area of Science:
- Virology
- Molecular Biology
- Immunology
Background:
- Influenza A virus (IAV) frequently develops resistance to antiviral drugs targeting viral proteins.
- There is a growing need for antiviral agents that target host cellular factors essential for virus replication.
- Tankyrase (TNKS), a negative regulator of host proteins, is being investigated for its role in viral infections.
Purpose of the Study:
- To investigate the role of Tankyrase 2 (TNKS2) in IAV infection.
- To identify microRNAs that target TNKS2.
- To elucidate the mechanisms by which TNKS2 influences IAV replication and host antiviral responses.
Main Methods:
- Quantitative analysis of TNKS2 expression in infected human lung epithelial cells and mouse lungs.
- RNA interference (RNAi) to knock down TNKS2 expression.
- Computational analysis and 3'-untranslation regions (3'-UTR) reporter assays to identify microRNA targets.
- Overexpression of miR-206 in cell culture and in vivo (adenovirus delivery to mouse lungs).
- Analysis of downstream signaling pathways (JNK/c-Jun, Type I Interferon, Stat signaling).
Main Results:
- TNKS2 expression is upregulated in lung tissues during IAV infection.
- Knockdown of TNKS2 significantly reduces IAV replication.
- miR-206 was identified as a direct targeting microRNA of TNKS2.
- Overexpression of miR-206 inhibits IAV replication in a strain-independent manner.
- miR-206 activates JNK/c-Jun signaling, induces Type I Interferon, and enhances Stat signaling.
- In vivo delivery of miR-206 suppresses viral load, boosts Type I Interferon response, and improves survival in IAV-infected mice.
Conclusions:
- miR-206 exhibits potent anti-influenza activity by targeting TNKS2.
- Targeting TNKS2 with miR-206 promotes an antiviral state in host cells.
- miR-206 represents a promising therapeutic candidate for treating influenza infections, including those resistant to conventional drugs.
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