The role of cellular chloride channels during human respiratory syncytial virus infection

Human respiratory syncytial virus (HRSV) is a common cause of respiratory tract infections (RTIs) globally. Of those infected, 25%–40% aged ≤1 year develop severe lower RTIs leading to pneumonia and bronchiolitis, with ~10% requiring hospitalisation. There is currently no HRSV vaccine and clinically approved treatments are only moderately effective. New and more effective anti-HRSV strategies are urgently required.
It is established that viruses require cellular ion channels to infect cells. Ion channels are a diverse class of transmembrane proteins that selectively allow ions across membranes, influencing a multitude of cellular processes. Modulation of these channels by viruses is an important host-pathogen interaction that regulates critical stages of the virus multiplication cycle including entry, replication, and egress.
Cellular chloride (Cl-) channels are large family of ion channels which were historically overlooked, however the importance of these proteins, especially within the respiratory tract, is now being revealed. This thesis examined the role of Cl- channels during HRSV infection. Utilising GFP-expressing HRSV in combination with an extensive panel of channel-specific pharmacological inhibitors, a critical requirement for calcium (Ca2+)-activated chloride channels (CaCCs) during HRSV infection was highlighted. For the first time, a role for TMEM16A as a host-factor was revealed and the channel was implicated as a post-exposure antiviral target.
An investigation into the mechanisms underpinning the relationship between HRSV and TMEM16A revealed that the channel was involved at the genome replication and/or transcription stage of infection, and evidence suggested that this interaction may occur at or near the Golgi, in HRSV replication factories.
Lastly, a role for TMEM16A was described within the HRSV-mediated production of antiviral protein interferon γ-induced protein 10 (IP-10), which supported a hypothesis wherein HRSV sequestered TMEM16A for genome replication, and simultaneously prevented the cellular antiviral response. Therefore, these findings have revealed TMEM16A as an exciting target for future host-directed antiviral therapeutics.