Dasatinib inhibits betacoronavirus replication in macrophages and attenuates pro-inflammatory mediators via SRC-MAPK...

Betacoronaviruses are emerging pathogens with pandemic potential, as shown by the recent COVID-19 pandemic caused by SARS-CoV-2. The replication of SARS-CoV-2 in monocytes and macrophages triggers the production of cytokines and chemokines, leading to a persistent inflammatory environment associated with increased disease severity. Dasatinib (DASA) is a broad-spectrum tyrosine kinase inhibitor that targets a wide range of tyrosine kinases, including ABL, SRC, c-KIT, PDGFR-α and ß, involved in the pathophysiology of various malignancies. Studies have reported additional mechanisms of action for DASA beyond the oncological context, including anti-inflammatory and antiviral effects. We investigated the potential of DASA as a promising therapeutic approach against betacoronavirus infections. Using an in vitro model of infection of RAW 264.7 cells with MHV-3, a betacoronavirus that mimics severe COVID-19 in murine models, we observed that both pre and post-infection treatment with DASA significantly reduced viral titers and pro-inflammatory mediators, such as IL-6, TNF, and CXCL2. Pre-treatment with DASA interfered with the early stages of the viral cycle in macrophages, such as viral adsorption and internalization, reducing viral titers. We demonstrated that SRC tyrosine kinase signaling is activated during MHV-3 infection. Post-infection treatment with DASA negatively modulated the SRC-MAPK-NF-ĸB signaling pathway, reducing the release of pro-inflammatory mediators by macrophages. Our data suggest the potential use of DASA as a promising adjuvant therapeutic strategy for treating coronavirus infections by negatively modulating SRC-mediated signaling pathways involved in inflammation and reducing MHV-3 replication. The results demonstrated that SRC signaling could be a target for interventions in controlling coronavirus infections.