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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.
- airway epithelium
- infection control
- paediatric lung disaese
- respiratory infection
- viral infection
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Footnotes
Contributors HP, EJAAT, MS, JDL, AW, JNB, CH and JM conceived the study. HP, EJAA, SEH and MA performed the experiments. All authors analysed and interpreted the data. All authors contributed to and approved the manuscript.
Funding The study was funded by the Royal Society (Fellowship RG110306 and UF100419) and the British Lung Foundation (BLF PPRG15-17).
Competing interests None declared.
Patient consent for publication Not required.
Ethics approval The use of human lung tissue was approved by the ethics committee (number 2701-2015) of the Hannover Medical School, Hanover, Germany. Experiments complied with the Code of Ethics of the World Medical Association (Declaration of Helsinki) involving human subjects. The privacy rights of human subjects were observed, and written consent was obtained from all patients. Personal data were not recorded to protect anonymity.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement Data are available upon reasonable request. All data relevant to the study are included in the article or uploaded as supplementary information. All free text entered below will be published.