PMID- 32992478
OWN - NLM
STAT- MEDLINE
DCOM- 20210216
LR  - 20221207
IS  - 1999-4915 (Electronic)
IS  - 1999-4915 (Linking)
VI  - 12
IP  - 10
DP  - 2020 Sep 27
TI  - Thapsigargin at Non-Cytotoxic Levels Induces a Potent Host Antiviral Response 
      that Blocks Influenza A Virus Replication.
LID - 10.3390/v12101093 [doi]
LID - 1093
AB  - 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) Ca(2+) 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.
FAU - Goulding, Leah V
AU  - Goulding LV
AD  - School of Veterinary Medicine and Science, University of Nottingham, Sutton 
      Bonington Campus, Sutton Bonington LE12 5RD, UK.
FAU - Yang, Jiayun
AU  - Yang J
AUID- ORCID: 0000-0002-9348-4336
AD  - School of Veterinary Medicine and Science, University of Nottingham, Sutton 
      Bonington Campus, Sutton Bonington LE12 5RD, UK.
FAU - Jiang, Zhimin
AU  - Jiang Z
AUID- ORCID: 0000-0002-9797-6493
AD  - Key Laboratory of Animal Epidemiology, Ministry of Agriculture, College of 
      Veterinary Medicine, China Agricultural University, No. 2 Yuanmingyuan West Road, 
      Beijing 100193, China.
FAU - Zhang, Hongyu
AU  - Zhang H
AD  - Key Laboratory of Animal Epidemiology, Ministry of Agriculture, College of 
      Veterinary Medicine, China Agricultural University, No. 2 Yuanmingyuan West Road, 
      Beijing 100193, China.
FAU - Lea, Daniel
AU  - Lea D
AUID- ORCID: 0000-0001-8152-0398
AD  - Advanced Data Analysis Centre, University of Nottingham, Sutton Bonington Campus, 
      Sutton Bonington LE12 5RD, UK.
FAU - Emes, Richard D
AU  - Emes RD
AD  - School of Veterinary Medicine and Science, University of Nottingham, Sutton 
      Bonington Campus, Sutton Bonington LE12 5RD, UK.
AD  - Advanced Data Analysis Centre, University of Nottingham, Sutton Bonington Campus, 
      Sutton Bonington LE12 5RD, UK.
FAU - Dottorini, Tania
AU  - Dottorini T
AUID- ORCID: 0000-0001-7733-906X
AD  - School of Veterinary Medicine and Science, University of Nottingham, Sutton 
      Bonington Campus, Sutton Bonington LE12 5RD, UK.
FAU - Pu, Juan
AU  - Pu J
AD  - Key Laboratory of Animal Epidemiology, Ministry of Agriculture, College of 
      Veterinary Medicine, China Agricultural University, No. 2 Yuanmingyuan West Road, 
      Beijing 100193, China.
FAU - Liu, Jinhua
AU  - Liu J
AD  - Key Laboratory of Animal Epidemiology, Ministry of Agriculture, College of 
      Veterinary Medicine, China Agricultural University, No. 2 Yuanmingyuan West Road, 
      Beijing 100193, China.
FAU - Chang, Kin-Chow
AU  - Chang KC
AUID- ORCID: 0000-0002-6602-7447
AD  - School of Veterinary Medicine and Science, University of Nottingham, Sutton 
      Bonington Campus, Sutton Bonington LE12 5RD, UK.
LA  - eng
GR  - MC_PC_18058/MRC_/Medical Research Council/United Kingdom
GR  - BB/L015293/1/BB_/Biotechnology and Biological Sciences Research Council/United 
      Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20200927
PL  - Switzerland
TA  - Viruses
JT  - Viruses
JID - 101509722
RN  - 0 (Antiviral Agents)
RN  - 0 (Interferon Type I)
RN  - 67526-95-8 (Thapsigargin)
RN  - 9008-11-1 (Interferons)
RN  - EC 3.6.3.8 (Sarcoplasmic Reticulum Calcium-Transporting ATPases)
RN  - 0 (Interferon Lambda)
SB  - IM
MH  - Animals
MH  - Antiviral Agents/*pharmacology
MH  - Cell Line
MH  - Chick Embryo
MH  - Chlorocebus aethiops
MH  - Dogs
MH  - Endoplasmic Reticulum Stress/drug effects
MH  - Female
MH  - Host-Pathogen Interactions/drug effects
MH  - Humans
MH  - Immunity, Innate/drug effects/immunology
MH  - Influenza A Virus, H1N1 Subtype/*growth & development
MH  - Influenza A Virus, H3N8 Subtype/*growth & development
MH  - Influenza, Human/drug therapy
MH  - Interferon Type I/drug effects/immunology
MH  - Interferons/drug effects/immunology
MH  - Mice
MH  - Mice, Inbred BALB C
MH  - Sarcoplasmic Reticulum Calcium-Transporting ATPases/antagonists & inhibitors
MH  - Swine
MH  - Thapsigargin/*pharmacology
MH  - Unfolded Protein Response/drug effects
MH  - Vero Cells
MH  - Virus Replication/*drug effects
MH  - Interferon Lambda
PMC - PMC7600819
OTO - NOTNLM
OT  - antiviral
OT  - endoplasmic reticulum stress
OT  - influenza A virus
OT  - innate immunity
OT  - thapsigargin
OT  - unfolded protein response
COIS- The authors declare no conflict of interest.
EDAT- 2020/10/01 06:00
MHDA- 2021/02/17 06:00
PMCR- 2020/10/01
CRDT- 2020/09/30 01:00
PHST- 2020/09/01 00:00 [received]
PHST- 2020/09/21 00:00 [revised]
PHST- 2020/09/24 00:00 [accepted]
PHST- 2020/09/30 01:00 [entrez]
PHST- 2020/10/01 06:00 [pubmed]
PHST- 2021/02/17 06:00 [medline]
PHST- 2020/10/01 00:00 [pmc-release]
AID - v12101093 [pii]
AID - viruses-12-01093 [pii]
AID - 10.3390/v12101093 [doi]
PST - epublish
SO  - Viruses. 2020 Sep 27;12(10):1093. doi: 10.3390/v12101093.