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.

• 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