Department of Pharmacology, School of Medicine of Ribeirao Preto, University of São Paulo, Ribeirao Preto, Brazil.
Department of Biochemistry and Immunology, School of Medicine of Ribeirao Preto, University of São Paulo, Ribeirao Preto, Brazil.
Front Immunol. 2020 Jan 31;10:3108. doi: 10.3389/fimmu.2019.03108. eCollection 2019.
The Chikungunya virus (CHIKV) is a re-emerging arbovirus, in which its infection causes a febrile illness also commonly associated with severe joint pain and myalgia. Although the immune response to CHIKV has been studied, a better understanding of the virus-host interaction mechanisms may lead to more effective therapeutic interventions. In this context, neutrophil extracellular traps (NETs) have been described as a key mediator involved in the control of many pathogens, including several bacteria and viruses, but no reports of this important protective mechanism were documented during CHIKV infection. Here we demonstrate that the experimental infection of mouse-isolated neutrophils with CHIKV resulted in NETosis (NETs release) through a mechanism dependent on TLR7 activation and reactive oxygen species generation. , mouse-isolated neutrophils stimulated with phorbol 12-myristate 13-acetate release NETs that once incubated with CHIKV, resulting in further virus capture and neutralization. , NETs inhibition by the treatment of the mice with DNase resulted in the enhanced susceptibility of IFNAR mice to CHIKV experimental acute infection. Lastly, by accessing the levels of MPO-DNA complex on the acutely CHIKV-infected patients, we found a correlation between the levels of NETs and the viral load in the blood, suggesting that NETs are also released in natural human infection cases. Altogether our findings characterize NETosis as a contributing natural process to control CHIKV acute infection, presenting an antiviral effect that helps to control systemic virus levels.
基孔肯雅病毒（CHIKV）是一种重新出现的虫媒病毒，其感染会导致发热疾病，通常还伴有严重的关节疼痛和肌肉疼痛。尽管已经研究了针对 CHIKV 的免疫反应，但更好地了解病毒-宿主相互作用机制可能会导致更有效的治疗干预。在这种情况下，中性粒细胞胞外陷阱（NETs）已被描述为参与控制许多病原体的关键介质，包括几种细菌和病毒，但在 CHIKV 感染期间没有记录到这种重要的保护机制的报道。在这里，我们证明通过 TLR7 激活和活性氧生成依赖的机制，用 CHIKV 感染分离的小鼠中性粒细胞会导致 NETosis（NET 释放）。此外，用佛波醇 12-肉豆蔻酸 13-乙酸刺激分离的小鼠中性粒细胞会释放 NETs，这些 NETs在与 CHIKV 孵育后，会进一步捕获和中和病毒。此外，通过用 DNase 处理小鼠来抑制 NETs 会导致 IFNAR 小鼠对 CHIKV 实验性急性感染的易感性增强。最后，通过检测急性感染 CHIKV 的患者中 MPO-DNA 复合物的水平，我们发现 NETs 的水平与血液中的病毒载量之间存在相关性，这表明在自然感染病例中也会释放 NETs。总之，我们的研究结果将 NETosis 确定为控制 CHIKV 急性感染的一种促进自然过程，表现出抗病毒作用，有助于控制系统病毒水平。
