Department of Medical Microbiology and Infection Prevention, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands.
Vaccine Development Laboratory, Microbiology Department, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil.
PLoS Pathog. 2022 Oct 14;18(10):e1010499. doi: 10.1371/journal.ppat.1010499. eCollection 2022 Oct.
Severe dengue virus (DENV) infection is characterized by exacerbated inflammatory responses that lead to endothelial dysfunction and plasma leakage. We have recently demonstrated that Toll-like receptor 2 (TLR2) on blood monocytes senses DENV infection leading to endothelial activation. Here, we report that non-infectious immature DENV particles, which are released in large numbers by DENV-infected cells, drive endothelial activation via the TLR2 axis. We show that fully immature DENV particles induce a rapid, within 6 hours post-infection, inflammatory response in PBMCs. Furthermore, pharmacological blocking of TLR2/TLR6/CD14 and/or NF-kB prior to exposure of PBMCs to immature DENV reduces the initial production of inter alia TNF-α and IL-1β by monocytes and prevents endothelial activation. However, prolonged TLR2 block induces TNF-α production and leads to exacerbated endothelial activation, indicating that TLR2-mediated responses play an important role not only in the initiation but also the resolution of inflammation. Altogether, these data indicate that the maturation status of the virus has the potential to influence the kinetics and extent of inflammatory responses during DENV infection.
重症登革热病毒（DENV）感染的特征是炎症反应加剧，导致血管内皮功能障碍和血浆渗漏。我们最近的研究表明，血液单核细胞上的 Toll 样受体 2（TLR2）可感知 DENV 感染，从而导致内皮细胞激活。在这里，我们报告说，大量由 DENV 感染细胞释放的无感染性不成熟 DENV 颗粒通过 TLR2 轴驱动内皮细胞激活。我们发现，完全不成熟的 DENV 颗粒在感染后 6 小时内即可引起 PBMC 中迅速的炎症反应。此外，在 PBMC 暴露于不成熟的 DENV 之前，通过药理学方法阻断 TLR2/TLR6/CD14 和/或 NF-kB，可减少单核细胞初始产生的 TNF-α和 IL-1β等细胞因子，并防止内皮细胞激活。然而，TLR2 的持续阻断会诱导 TNF-α的产生，并导致内皮细胞激活加剧，表明 TLR2 介导的反应不仅在炎症的起始阶段，而且在炎症的消退阶段都发挥着重要作用。总之，这些数据表明，病毒的成熟状态有可能影响 DENV 感染期间炎症反应的动力学和程度。
