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Article

Thapsigargin at Non-Cytotoxic Levels Induces a Potent Host Antiviral Response that Blocks Influenza A Virus Replication

1
School of Veterinary Medicine and Science, University of Nottingham, Sutton Bonington Campus, Sutton Bonington LE12 5RD, UK
2
Key Laboratory of Animal Epidemiology, Ministry of Agriculture, College of Veterinary Medicine, China Agricultural University, No. 2 Yuanmingyuan West Road, Beijing 100193, China
3
Advanced Data Analysis Centre, University of Nottingham, Sutton Bonington Campus, Sutton Bonington LE12 5RD, UK
*
Author to whom correspondence should be addressed.
Viruses 2020, 12(10), 1093; https://doi.org/10.3390/v12101093
Received: 1 September 2020 / Revised: 21 September 2020 / Accepted: 24 September 2020 / Published: 27 September 2020
(This article belongs to the Section Viral Immunology, Vaccines, and Antivirals)
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. View Full-Text
Keywords: thapsigargin; endoplasmic reticulum stress; unfolded protein response; antiviral; influenza A virus; innate immunity thapsigargin; endoplasmic reticulum stress; unfolded protein response; antiviral; influenza A virus; innate immunity
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MDPI and ACS Style

Goulding, L.V.; Yang, J.; Jiang, Z.; Zhang, H.; Lea, D.; Emes, R.D.; Dottorini, T.; Pu, J.; Liu, J.; Chang, K.-C. Thapsigargin at Non-Cytotoxic Levels Induces a Potent Host Antiviral Response that Blocks Influenza A Virus Replication. Viruses 2020, 12, 1093. https://doi.org/10.3390/v12101093

AMA Style

Goulding LV, Yang J, Jiang Z, Zhang H, Lea D, Emes RD, Dottorini T, Pu J, Liu J, Chang K-C. Thapsigargin at Non-Cytotoxic Levels Induces a Potent Host Antiviral Response that Blocks Influenza A Virus Replication. Viruses. 2020; 12(10):1093. https://doi.org/10.3390/v12101093

Chicago/Turabian Style

Goulding, Leah V., Jiayun Yang, Zhimin Jiang, Hongyu Zhang, Daniel Lea, Richard D. Emes, Tania Dottorini, Juan Pu, Jinhua Liu, and Kin-Chow Chang. 2020. "Thapsigargin at Non-Cytotoxic Levels Induces a Potent Host Antiviral Response that Blocks Influenza A Virus Replication" Viruses 12, no. 10: 1093. https://doi.org/10.3390/v12101093

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