ERJ open research · 2025
B-Raf kinase blockade protects airway epithelial cells against respiratory syncytial virus infection and modulates interferon responses.
СтатьяНазвание и аннотация: Перевод в очереди
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Cerato Julia A, Serda Maria, Olumade Testimony, Duan Wenming, Thanikachalam Sowmya, Salih Rasha, Madlangsakay Ma Immanuel Reyes, Moraes Theo J, Santer Deanna M, Zahedi Rene P, Coombs Kevin M, Porto Barbara N
Аннотация
BACKGROUND: Respiratory syncytial virus (RSV) is the primary cause of hospitalisation due to acute bronchiolitis and viral pneumonia in infants and young children. Recently, a maternal RSV vaccine (Pfizer's Abrysvo) has been approved to protect infants from birth up to 6 months of age. However, there is currently no vaccine or antiviral therapy against RSV for children aged >6 months. Therefore, there is an urgent need for novel antiviral therapies against RSV infection for young children.
METHODS: We hypothesised that blocking a host protein called B-Raf kinase would inhibit RSV replication and protect airway epithelial cells against infection. We investigated the in vitro effects of dabrafenib, a US Food and Drug Administration-approved B-Raf kinase inhibitor, against RSV. Human airway epithelial cell lines and primary nasal epithelial cells were infected with RSV and treated with dabrafenib. Real-time PCR, plaque assay, quantitative mass spectrometry, ELISA and immunofluorescence were performed.
RESULTS: Dabrafenib impaired RSV infection and replication (p=0.0003), while protecting cells against RSV-induced lytic cell death (p<0.0001). Proteomics and PCR analyses revealed that dabrafenib decreased the expression of the interferon-stimulated genes IFIT1 (p<0.0001) and ISG15 (p<0.0001) and corresponding proteins in airway epithelial cells. Therapeutic treatment with dabrafenib differentially modulated the release of type I and III interferons.
CONCLUSIONS: Collectively, our data indicate that B-Raf kinase is involved in RSV replication, interferon-stimulated gene induction, and type I and III interferon release in airway epithelial cells following infection. We propose that repurposing dabrafenib as a host-directed antiviral against RSV may be valuable in reducing disease pathogenesis associated with RSV infection.
METHODS: We hypothesised that blocking a host protein called B-Raf kinase would inhibit RSV replication and protect airway epithelial cells against infection. We investigated the in vitro effects of dabrafenib, a US Food and Drug Administration-approved B-Raf kinase inhibitor, against RSV. Human airway epithelial cell lines and primary nasal epithelial cells were infected with RSV and treated with dabrafenib. Real-time PCR, plaque assay, quantitative mass spectrometry, ELISA and immunofluorescence were performed.
RESULTS: Dabrafenib impaired RSV infection and replication (p=0.0003), while protecting cells against RSV-induced lytic cell death (p<0.0001). Proteomics and PCR analyses revealed that dabrafenib decreased the expression of the interferon-stimulated genes IFIT1 (p<0.0001) and ISG15 (p<0.0001) and corresponding proteins in airway epithelial cells. Therapeutic treatment with dabrafenib differentially modulated the release of type I and III interferons.
CONCLUSIONS: Collectively, our data indicate that B-Raf kinase is involved in RSV replication, interferon-stimulated gene induction, and type I and III interferon release in airway epithelial cells following infection. We propose that repurposing dabrafenib as a host-directed antiviral against RSV may be valuable in reducing disease pathogenesis associated with RSV infection.