Pearson, H orcid.org/0000-0001-6591-9884, Todd, EJAA orcid.org/0000-0003-0011-262X, Ahrends, M et al. (10 more authors) (2021) TMEM16A/ANO1 calcium-activated chloride channel as a novel target for the treatment of human respiratory syncytial virus infection. Thorax, 76 (1). pp. 64-72. ISSN 0040-6376
Abstract
Introduction: Human respiratory syncytial virus (HRSV) is a common cause of respiratory tract infections (RTIs) globally and is one of the most fatal infectious diseases for infants in developing countries. Of those infected, 25%–40% aged ≤1 year develop severe lower RTIs leading to pneumonia and bronchiolitis, with ~10% requiring hospitalisation. Evidence also suggests that HRSV infection early in life is a major cause of adult asthma. There is no HRSV vaccine, and the only clinically approved treatment is immunoprophylaxis that is expensive and only moderately effective. New anti-HRSV therapeutic strategies are therefore urgently required.
Methods: It is now established that viruses require cellular ion channel functionality to infect cells. Here, we infected human lung epithelial cell lines and ex vivo human lung slices with HRSV in the presence of a defined panel of chloride (Cl−) channel modulators to investigate their role during the HRSV life-cycle.
Results: We demonstrate the requirement for TMEM16A, a calcium-activated Cl− channel, for HRSV infection. Time-of-addition assays revealed that the TMEM16A blockers inhibit HRSV at a postentry stage of the virus life-cycle, showing activity as a postexposure prophylaxis. Another important negative-sense RNA respiratory pathogen influenza virus was also inhibited by the TMEM16A-specific inhibitor T16Ainh-A01.
Discussion: These findings reveal TMEM16A as an exciting target for future host-directed antiviral therapeutics.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © Author(s) (or their employer(s)) 2020. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) (https://creativecommons.org/licenses/by-nc/4.0/) |
Dates: |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Biological Sciences (Leeds) > School of Biomedical Sciences (Leeds) The University of Leeds > Faculty of Biological Sciences (Leeds) > School of Molecular and Cellular Biology (Leeds) > Molecular Biology (Leeds) |
Funding Information: | Funder Grant number Royal Society RG110306 Royal Society UF100419 British Lung Foundation PPRG15-17 |
Depositing User: | Symplectic Publications |
Date Deposited: | 16 Sep 2020 15:31 |
Last Modified: | 10 Nov 2021 13:42 |
Status: | Published |
Publisher: | BMJ Publishing Group |
Identification Number: | 10.1136/thoraxjnl-2020-215171 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:165590 |