Guangdong Provincial Key Laboratory of Virology, Institute of Medical Microbiology, Jinan University, Guangzhou, China.
The First Affiliated Hospital of Jinan University, Guangzhou, China.
PLoS Pathog. 2021 Jul 26;17(7):e1008603. doi: 10.1371/journal.ppat.1008603. eCollection 2021 Jul.
Dengue virus (DENV) is a mosquito-borne pathogen that causes a spectrum of diseases including life-threatening dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS). Vascular leakage is a common clinical crisis in DHF/DSS patients and highly associated with increased endothelial permeability. The presence of vascular leakage causes hypotension, circulatory failure, and disseminated intravascular coagulation as the disease progresses of DHF/DSS patients, which can lead to the death of patients. However, the mechanisms by which DENV infection caused the vascular leakage are not fully understood. This study reveals a distinct mechanism by which DENV induces endothelial permeability and vascular leakage in human endothelial cells and mice tissues. We initially show that DENV2 promotes the matrix metalloproteinase-9 (MMP-9) expression and secretion in DHF patients' sera, peripheral blood mononuclear cells (PBMCs), and macrophages. This study further reveals that DENV non-structural protein 1 (NS1) induces MMP-9 expression through activating the nuclear factor κB (NF-κB) signaling pathway. Additionally, NS1 facilitates the MMP-9 enzymatic activity, which alters the adhesion and tight junction and vascular leakage in human endothelial cells and mouse tissues. Moreover, NS1 recruits MMP-9 to interact with β-catenin and Zona occludens protein-1/2 (ZO-1 and ZO-2) and to degrade the important adhesion and tight junction proteins, thereby inducing endothelial hyperpermeability and vascular leakage in human endothelial cells and mouse tissues. Thus, we reveal that DENV NS1 and MMP-9 cooperatively induce vascular leakage by impairing endothelial cell adhesion and tight junction, and suggest that MMP-9 may serve as a potential target for the treatment of hypovolemia in DSS/DHF patients.
登革热病毒（DENV）是一种经蚊子传播的病原体，可引起一系列疾病，包括危及生命的登革出血热（DHF）和登革休克综合征（DSS）。血管渗漏是 DHF/DSS 患者常见的临床危象，与内皮通透性增加高度相关。随着 DHF/DSS 患者病情的发展，血管渗漏会导致低血压、循环衰竭和弥散性血管内凝血，这可能导致患者死亡。然而，DENV 感染导致血管渗漏的机制尚未完全阐明。本研究揭示了 DENV 诱导人内皮细胞和小鼠组织中内皮通透性和血管渗漏的独特机制。我们最初表明，DENV2 促进 DHF 患者血清、外周血单核细胞（PBMC）和巨噬细胞中基质金属蛋白酶-9（MMP-9）的表达和分泌。本研究进一步表明，DENV 非结构蛋白 1（NS1）通过激活核因子 κB（NF-κB）信号通路诱导 MMP-9 的表达。此外，NS1 促进 MMP-9 的酶活性，改变人内皮细胞和小鼠组织中的黏附和紧密连接，导致血管渗漏。此外，NS1 招募 MMP-9 与β-连环蛋白和紧密连接蛋白 1/2（ZO-1 和 ZO-2）相互作用，并降解重要的黏附和紧密连接蛋白，从而诱导人内皮细胞和小鼠组织中的内皮细胞高通透性和血管渗漏。因此，我们揭示了 DENV NS1 和 MMP-9 通过破坏内皮细胞黏附和紧密连接共同诱导血管渗漏，并表明 MMP-9 可能作为治疗 DSS/DHF 患者低血容量的潜在靶点。
