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B-Raf kinase blockade protects airway epithelial cells against respiratory syncytial virus infection and modulates interferon responses
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DOI：10.1183/23120541.00307-2025.png)
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Abstract
En 中文
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.
Keywords:
MIXED LINEAGE KINASE
INFLUENZA-VIRUS
DOMAIN-LIKE
IN-VITRO
EXPRESSION
DOWNSTREAM
DABRAFENIB
RSV
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