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TMEM16A/ANO1 calcium-activated chloride channel as a novel target for the treatment of human respiratory syncytial virus infection.
Thorax. 2020 Oct 27 [Online ahead of print]T

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.

Authors+Show Affiliations

University of Leeds, Leeds, UK.University of Leeds, Leeds, UK.Fraunhofer Institute for Toxicology and Experimental Medicine, Hanover, Germany.University of Leeds, Leeds, UK.University of Leeds, Leeds, UK.University of Leeds, Leeds, UK.University of Leeds, Leeds, UK. School of Biomedical Sciences, University of Leeds, Leeds, UK.KRH Clinics Hanover, Hanover, Germany.KRH Clinics Hanover, Hanover, Germany.Fraunhofer Institute for Toxicology and Experimental Medicine, Hanover, Germany.Fraunhofer Institute for Toxicology and Experimental Medicine, Hanover, Germany.University of Leeds, Leeds, UK j.mankouri@leeds.ac.uk J.n.Barr@leeds.ac.uk.University of Leeds, Leeds, UK j.mankouri@leeds.ac.uk J.n.Barr@leeds.ac.uk.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

33109690

Citation

Pearson, Hayley, et al. "TMEM16A/ANO1 Calcium-activated Chloride Channel as a Novel Target for the Treatment of Human Respiratory Syncytial Virus Infection." Thorax, 2020.
Pearson H, Todd EJAA, Ahrends M, et al. TMEM16A/ANO1 calcium-activated chloride channel as a novel target for the treatment of human respiratory syncytial virus infection. Thorax. 2020.
Pearson, H., Todd, E. J. A. A., Ahrends, M., Hover, S. E., Whitehouse, A., Stacey, M., Lippiat, J. D., Wilkens, L., Fieguth, H. G., Danov, O., Hesse, C., Barr, J. N., & Mankouri, J. (2020). TMEM16A/ANO1 calcium-activated chloride channel as a novel target for the treatment of human respiratory syncytial virus infection. Thorax. https://doi.org/10.1136/thoraxjnl-2020-215171
Pearson H, et al. TMEM16A/ANO1 Calcium-activated Chloride Channel as a Novel Target for the Treatment of Human Respiratory Syncytial Virus Infection. Thorax. 2020 Oct 27; PubMed PMID: 33109690.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - TMEM16A/ANO1 calcium-activated chloride channel as a novel target for the treatment of human respiratory syncytial virus infection. AU - Pearson,Hayley, AU - Todd,Eleanor J A A, AU - Ahrends,Mareike, AU - Hover,Samantha E, AU - Whitehouse,Adrian, AU - Stacey,Martin, AU - Lippiat,Jonathan D, AU - Wilkens,Ludwig, AU - Fieguth,Hans-Gerd, AU - Danov,Olga, AU - Hesse,Christina, AU - Barr,John N, AU - Mankouri,Jamel, Y1 - 2020/10/27/ PY - 2020/04/30/received PY - 2020/08/27/revised PY - 2020/09/07/accepted PY - 2020/10/28/entrez PY - 2020/10/29/pubmed PY - 2020/10/29/medline KW - airway epithelium KW - infection control KW - paediatric lung disaese KW - respiratory infection KW - viral infection JF - Thorax JO - Thorax N2 - 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. SN - 1468-3296 UR - https://www.unboundmedicine.com/medline/citation/33109690/TMEM16A/ANO1_calcium-activated_chloride_channel_as_a_novel_target_for_the_treatment_of_human_respiratory_syncytial_virus_infection L2 - https://thorax.bmj.com/lookup/pmidlookup?view=long&pmid=33109690 DB - PRIME DP - Unbound Medicine ER -
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