Thapsigargin at non-cytotoxic levels induces a potent host antiviral response that blocks influenza a virus replication

Goulding, Leah V.; Yang, Jiayun; Jiang, Zhimin; Zhang, Hongyu; Lea, Daniel; Emes, Richard D.; Dottorini, Tania; Pu, Juan; Liu, Jinhua; Chang, Kin Chow

Abstract

© 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). Influenza A virus is a major global pathogen of humans, and there is an unmet need for effective antivirals. Current antivirals against influenza A virus directly target the virus and are vulnerable to mutational resistance. Harnessing an effective host antiviral response is an attractive alternative. We show that brief exposure to low, non-toxic doses of thapsigargin (TG), an inhibitor of the sarcoplasmic/endoplasmic reticulum (ER) Ca2+ ATPase pump, promptly elicits an extended antiviral state that dramatically blocks influenza A virus production. Crucially, oral administration of TG protected mice against lethal virus infection and reduced virus titres in the lungs of treated mice. TG-induced ER stress unfolded protein response appears as a key driver responsible for activating a spectrum of host antiviral defences that include an enhanced type I/III interferon response. Our findings suggest that TG is potentially a viable host-centric antiviral for the treatment of influenza A virus infection without the inherent problem of drug resistance.

Citation

Goulding, L. V., Yang, J., Jiang, Z., Zhang, H., Lea, D., Emes, R. D., …Chang, K. C. (2020). Thapsigargin at non-cytotoxic levels induces a potent host antiviral response that blocks influenza a virus replication. Viruses, 12(10), Article 1093. https://doi.org/10.3390/v12101093

• Journal Article Type: Article
• Acceptance Date: Sep 24, 2020
• Online Publication Date: Sep 27, 2020
• Publication Date: Oct 1, 2020
• Deposit Date: Sep 28, 2020
• Publicly Available Date: Sep 28, 2020
• Journal: Viruses
• Electronic ISSN: 1999-4915
• Publisher: MDPI
• Peer Reviewed: Peer Reviewed
• Volume: 12
• Issue: 10
• Article Number: 1093
• DOI: https://doi.org/10.3390/v12101093
• Keywords: thapsigargin; endoplasmic reticulum stress; unfolded protein response; antiviral; influenza A virus; innate immunity
• Public URL: https://nottingham-repository.worktribe.com/output/4932393
• Publisher URL: https://www.mdpi.com/1999-4915/12/10/1093/htm