Ricoy Ana Carolina Santos, Braga Marina Pimenta, Lacerda Thaís Targino Ferreira, Martins Flávia Rayssa Braga, Mendes Ana Clara, Teixeira Mauro Martins, Costa Vivian Vasconcelos, Bahia Diana, Soriani Frederico Marianetti
Departamento de Genética, Ecologia e Evolução, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.
Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.
Med Microbiol Immunol. 2025 Aug 27;214(1):37. doi: 10.1007/s00430-025-00850-2.
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.
β冠状病毒是具有大流行潜力的新兴病原体，最近由严重急性呼吸综合征冠状病毒2（SARS-CoV-2）引起的2019冠状病毒病（COVID-19）大流行就证明了这一点。SARS-CoV-2在单核细胞和巨噬细胞中的复制会触发细胞因子和趋化因子的产生，导致与疾病严重程度增加相关的持续性炎症环境。达沙替尼（DASA）是一种广谱酪氨酸激酶抑制剂，可靶向多种酪氨酸激酶，包括ABL、SRC、c-KIT、血小板衍生生长因子受体α（PDGFR-α）和β，这些激酶参与各种恶性肿瘤的病理生理过程。研究报告了达沙替尼在肿瘤学背景之外的其他作用机制，包括抗炎和抗病毒作用。我们研究了达沙替尼作为一种有前景的治疗方法对抗β冠状病毒感染的潜力。使用RAW 264.7细胞感染鼠肝炎病毒3型（MHV-3，一种在小鼠模型中模拟严重COVID-19的β冠状病毒）的体外感染模型，我们观察到达沙替尼在感染前和感染后治疗均显著降低了病毒滴度以及促炎介质，如白细胞介素-6（IL-6）、肿瘤坏死因子（TNF）和CXC趋化因子配体2（CXCL2）。达沙替尼预处理会干扰巨噬细胞中病毒周期的早期阶段，如病毒吸附和内化，从而降低病毒滴度。我们证明在MHV-3感染期间SRC酪氨酸激酶信号被激活。达沙替尼感染后治疗会负向调节SRC-丝裂原活化蛋白激酶（MAPK）-核因子κB（NF-κB）信号通路，减少巨噬细胞促炎介质的释放。我们的数据表明，达沙替尼有可能作为一种有前景的辅助治疗策略，通过负向调节参与炎症的SRC介导的信号通路并减少MHV-3复制来治疗冠状病毒感染。结果表明，SRC信号可能是控制冠状病毒感染干预措施的一个靶点。
