A Critical Role for Perivascular Cells in Amplifying Vascular Leakage Induced by Dengue Virus Nonstructural Protein 1.
A Critical Role for Perivascular Cells in Amplifying Vascular Leakage Induced by Dengue Virus Nonstructural Protein 1.
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DOI：
10.1128/msphere.00258-20
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发表时间：
2020-08-05
期刊：
影响因子：
4.8
通讯作者：
Campagnolo P
中科院分区：
文献类型：
--
作者：
Cheung YP;Mastrullo V;Maselli D;Butsabong T;Madeddu P;Maringer K;Campagnolo P
登革热是影响人类的最流行的节肢动物传播的病毒性疾病，严重的登革热的典型特征是潜在致命的微血管渗漏和低血容量性休克。微脉管系统的血管由血管周围细胞（周细胞）包裹的内皮细胞的管状结构组成。周细胞通过旁分泌和接触介导的信号传导支持内皮细胞屏障的形成和维持，并且对于微血管的完整性至关重要。周细胞功能障碍与糖尿病视网膜病变等非传染性疾病中的血管渗漏有关，但从未与感染相关的血管渗漏有关。登革热血管渗漏已被证明部分是由分泌性登革热病毒 (DENV) 非结构蛋白 NS1 对内皮细胞的直接作用造成的。使用原代人类血管细胞，我们在此表明 NS1 也会导致周细胞功能障碍，并且 NS1 诱导的内皮通透性过高在周细胞存在的情况下更加明显。值得注意的是，在三维 (3D) 微血管测定中，NS1 特异性破坏了周细胞支持内皮细胞功能的能力，但对周细胞活力或生理没有影响。这些效应至少部分是通过参与周细胞内皮屏障维持的接触独立的旁分泌信号介导的。因此，我们确定了周细胞在放大严重登革热中 NS1 诱导的微血管通透性过高中的作用，从而表明周细胞在传染性血管渗漏综合征的病因学中发挥着关键作用。这些发现为开发抗击感染引起的血管渗漏（例如严重登革热）的药物和诊断方法开辟了新的研究途径。重要性 世界卫生组织将登革热视为全球十大公共卫生问题之一。目前尚无治疗登革热病毒的特异性抗病毒疗法，也无法预测哪些患者将患上潜在致命的严重登革热，其典型症状是血管渗漏和循环性休克。我们在此表明，血管周围细胞（周细胞）通过向内皮细胞发出不依赖接触的信号，放大了登革热病毒蛋白 NS1 的血管渗漏诱导作用。虽然已知周细胞会导致非传染性血管渗漏，但这是第一次将这些细胞涉及传染病的血管效应。我们的研究结果可能为对抗登革热和其他潜在传染性血管渗漏综合征的新疗法和诊断方法铺平道路。
Dengue is the most prevalent arthropod-borne viral disease affecting humans, with severe dengue typified by potentially fatal microvascular leakage and hypovolemic shock. Blood vessels of the microvasculature are composed of a tubular structure of endothelial cells ensheathed by perivascular cells (pericytes). Pericytes support endothelial cell barrier formation and maintenance through paracrine and contact-mediated signaling and are critical to microvascular integrity. Pericyte dysfunction has been linked to vascular leakage in noncommunicable pathologies such as diabetic retinopathy but has never been linked to infection-related vascular leakage. Dengue vascular leakage has been shown to result in part from the direct action of the secreted dengue virus (DENV) nonstructural protein NS1 on endothelial cells. Using primary human vascular cells, we show here that NS1 also causes pericyte dysfunction and that NS1-induced endothelial hyperpermeability is more pronounced in the presence of pericytes. Notably, NS1 specifically disrupted the ability of pericytes to support endothelial cell function in a three-dimensional (3D) microvascular assay, with no effect on pericyte viability or physiology. These effects are mediated at least in part through contact-independent paracrine signals involved in endothelial barrier maintenance by pericytes. We therefore identify a role for pericytes in amplifying NS1-induced microvascular hyperpermeability in severe dengue and thus show that pericytes can play a critical role in the etiology of an infectious vascular leakage syndrome. These findings open new avenues of research for the development of drugs and diagnostic assays for combating infection-induced vascular leakage, such as severe dengue. IMPORTANCE The World Health Organization considers dengue one of the top 10 global public health problems. There is no specific antiviral therapy to treat dengue virus and no way of predicting which patients will develop potentially fatal severe dengue, typified by vascular leakage and circulatory shock. We show here that perivascular cells (pericytes) amplify the vascular leakage-inducing effects of the dengue viral protein NS1 through contact-independent signaling to endothelial cells. While pericytes are known to contribute to noncommunicable vascular leakage, this is the first time these cells have been implicated in the vascular effects of an infectious disease. Our findings could pave the way for new therapies and diagnostics to combat dengue and potentially other infectious vascular leakage syndromes.