Journal article
Influenza A Viral Replication Is Blocked by Inhibition of the Inositol-requiring Enzyme 1 (IRE1) Stress Pathway
The Journal of biological chemistry, Vol.287(7), pp.4679-4689
02/10/2012
DOI: 10.1074/jbc.M111.284695
PMCID: PMC3281634
PMID: 22194594
Abstract
Background:
The role of endoplasmic reticulum (ER) stress in influenza A viral infection is unknown.
Results:
Influenza A virus induces the IRE1 pathway of the ER stress response. Inhibition of IRE1 activity leads to decreased viral replication.
Conclusion:
IRE1 is a potential therapeutic target for influenza A virus.
Significance:
Targeting a host molecular mechanism is a novel therapeutic strategy that is less likely to be invalidated by viral mutagenesis.
Known therapies for influenza A virus infection are complicated by the frequent emergence of resistance. A therapeutic strategy that may escape viral resistance is targeting host cellular mechanisms involved in viral replication and pathogenesis. The endoplasmic reticulum (ER) stress response, also known as the unfolded protein response (UPR), is a primitive, evolutionary conserved molecular signaling cascade that has been implicated in multiple biological phenomena including innate immunity and the pathogenesis of certain viral infections. We investigated the effect of influenza A viral infection on ER stress pathways in lung epithelial cells. Influenza A virus induced ER stress in a pathway-specific manner. We showed that the virus activates the IRE1 pathway with little or no concomitant activation of the PERK and the ATF6 pathways. When we examined the effects of modulating the ER stress response on the virus, we found that the molecular chaperone tauroursodeoxycholic acid (TUDCA) significantly inhibits influenza A viral replication. In addition, a specific inhibitor of the IRE1 pathway also blocked viral replication. Our findings constitute the first evidence that ER stress plays a role in the pathogenesis of influenza A viral infection. Decreasing viral replication by modulating the host ER stress response is a novel strategy that has important therapeutic implications.
Details
- Title: Subtitle
- Influenza A Viral Replication Is Blocked by Inhibition of the Inositol-requiring Enzyme 1 (IRE1) Stress Pathway
- Creators
- Ihab H Hassan - From theMichael S Zhang - From theLinda S Powers - From theJian Q Shao - Central Microscopy Research FacilityJonas Baltrusaitis - Central Microscopy Research FacilityD. Thomas Rutkowski - Department of Anatomy and Cell Biology, andKevin Legge - Department of Pathology, University of Iowa, Iowa City, Iowa 52242Martha M Monick - From the
- Resource Type
- Journal article
- Publication Details
- The Journal of biological chemistry, Vol.287(7), pp.4679-4689
- DOI
- 10.1074/jbc.M111.284695
- PMID
- 22194594
- PMCID
- PMC3281634
- NLM abbreviation
- J Biol Chem
- ISSN
- 0021-9258
- eISSN
- 1083-351X
- Publisher
- American Society for Biochemistry and Molecular Biology; 9650 Rockville Pike, Bethesda, MD 20814, U.S.A
- Grant note
- R01 HL079901; R01 HL 096625; R21 HL109589 / National Institutes of Health
- Alternative title
- Influenza A Virus and ER Stress
- Language
- English
- Date published
- 02/10/2012
- Academic Unit
- Pulmonary, Critical Care, and Occupational Medicine; Microbiology and Immunology; Anatomy and Cell Biology; Pathology; Internal Medicine
- Record Identifier
- 9984047669202771
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