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A High Resolution Method to Monitor Phosphorylation-dependent Activation of IRF3
Published on: January 24, 2016
miR-144 attenuates the host response to influenza virus by targeting the TRAF6-IRF7 signaling axis
Carrie M Rosenberger1, Rebecca L Podyminogin1, Alan H Diercks1
1Center for Infectious Disease Research, Seattle, WA United States of America.
Abstract:
Antiviral responses must rapidly defend against infection while minimizing inflammatory damage, but the mechanisms that regulate the magnitude of response within an infected cell are not well understood. miRNAs are small non-coding RNAs that suppress protein levels by binding target sequences on their cognate mRNA. Here, we identify miR-144 as a negative regulator of the host antiviral response. Ectopic expression of miR-144 resulted in increased replication of three RNA viruses in primary mouse lung epithelial cells: influenza virus, EMCV, and VSV. We identified the transcriptional network regulated by miR-144 and demonstrate that miR-144 post-transcriptionally suppresses TRAF6 levels. In vivo ablation of miR-144 reduced influenza virus replication in the lung and disease severity. These data suggest that miR-144 reduces the antiviral response by attenuating the TRAF6-IRF7 pathway to alter the cellular antiviral transcriptional landscape.
Insights
MicroRNAs (miRNAs) regulate cellular responses. This study identifies miR-144 as a key negative regulator of the host antiviral response, impacting viral replication and disease severity.
Area of Science:
- Virology
- Molecular Biology
- Immunology
Background:
- Antiviral responses are crucial for host defense but require tight regulation to prevent excessive inflammation.
- MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression post-transcriptionally.
- Mechanisms controlling the magnitude of antiviral responses within infected cells remain incompletely understood.
Purpose of the Study:
- To identify novel regulators of the host antiviral response.
- To investigate the role of microRNAs in modulating antiviral immunity.
- To elucidate the specific molecular pathways targeted by identified regulators.
Main Methods:
- Ectopic expression of miR-144 in primary mouse lung epithelial cells.
- Assessment of viral replication for influenza virus, EMCV, and VSV.
- Identification of the transcriptional network regulated by miR-144.
- Analysis of TRAF6 and IRF7 pathway involvement.
- In vivo studies using miR-144 knockout mice to evaluate influenza virus infection.
Main Results:
- Ectopic miR-144 expression enhanced replication of multiple RNA viruses (influenza, EMCV, VSV).
- miR-144 was found to post-transcriptionally suppress levels of TRAF6 (TNF receptor-associated factor 6).
- In vivo ablation of miR-144 significantly reduced influenza virus replication and disease severity in mouse lungs.
- miR-144 attenuates the TRAF6-IRF7 pathway, altering the cellular antiviral transcriptional landscape.
Conclusions:
- miR-144 acts as a negative regulator of the host antiviral response.
- Suppression of TRAF6 by miR-144 dampens the antiviral signaling cascade.
- Targeting miR-144 may represent a therapeutic strategy to enhance antiviral immunity and reduce disease severity.
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