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

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

Research output: Journal PublicationArticlepeer-review

10 Citations (Scopus)

Abstract

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.

Original languageEnglish
Article number1093
JournalViruses
Volume12
Issue number10
DOIs
Publication statusPublished - Oct 2020
Externally publishedYes

Keywords

  • Antiviral
  • Endoplasmic reticulum stress
  • Influenza A virus
  • Innate immunity
  • Thapsigargin
  • Unfolded protein response

ASJC Scopus subject areas

  • Infectious Diseases
  • Virology

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