THE ROLE OF PERIVASCULAR CELL (PERICYTE) DYSFUNCTION IN HEPATIC COMPLICATIONS OF SEVERE DENGUE

血管周围细胞（周细胞）功能障碍在严重登革热肝脏并发症中的作用

• 批准号: MR/X009203/1
• 负责人: Paola Campagnolo
• 金额: $ 78.53万
• 依托单位: University of Surrey
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2024
• 资助国家: 英国
• 起止时间: 2024 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FX009203%2F1
• 关键词: ROLE; PERIVASCULAR; CELL; PERICYTE; DYSFUNCTION

The World Health Organisation listed dengue as one of its top ten threats to global public health in 2019, comparable to climate change and antimicrobial resistance, and one of only three infectious diseases on the list. Half of the world's population is at risk of dengue virus infection, mostly in low- and middle-income countries. Dengue disease normally manifest as a febrile syndrome, but in some patients the disease progresses into a severe phase presenting with generalised and acute blood and fluid leakage from blood vessels that can lead to systemic shock and death. With the current vaccine unsuitable for use in all settings, no specific antiviral drugs, and no prognostic markers to identify patients that will progress to severe disease, dengue poses an enormous health, economic and social burden on the affected countries and individuals.The liver is often compromised in severe dengue patients, leading to fluid accumulation in the abdomen and local haemorrhage; indeed, biomarkers of liver dysfunction correlate with dengue disease severity and a poor prognostic outcome. The ways in which severe dengue disease affects the liver, and in particular its vasculature, are not entirely understood at a mechanistic level and might provide important clues to identify patients at high risk of developing severe disease, and new ways of developing drugs to improve patient outcomes. This project will focus on understanding the development of blood vessel malfunction in the liver of severe dengue patients by focusing on the biology of the blood vessels affected by dengue haemorrhage. Liver blood vessels are formed of two cell types, endothelial cells lining the inner surface of the vessel and perivascular cells (hepatic stellate cells) enveloping the endothelial tubes. The function of pericytes is to closely regulate the function of endothelial cells and modulate the integrity of blood vessel. Our own research has shown for the first time that the presence of a viral protein called 'NS1', which is present in high concentration in the blood of severe dengue patients, prevents pericytes from performing this regulatory function. Indeed, our experiments showed that the NS1 protein disrupts the interaction between endothelial cells and pericytes, leaving the endothelial vessels naked and leaky because they lack pericytes. In this grant, we propose to study three separate ways in which dengue virus might be causing the dysfunction of liver hepatic stellate cells, and therefore provoking vessel leakage: (1) the impact of the NS1 protein present in patient blood, (2) direct infection of hepatic stellate cells by dengue virus, and (3) the release of inflammatory substances by infected liver cells (hepatocytes). While investigating these mechanisms, we will focus on how they change the identity of the hepatic stellate cells by causing their differentiation into different cell type and how they modify the hepatic stellate cells' relationship with blood vessels, affecting the integrity of the blood vessel barrier. Furthermore, we will investigate the behaviour of all four variants dengue viruses (serotypes) as the presentation of severe symptoms has been reported to differ depending on the predominant variant in each outbreak.

世界卫生组织将登革热列为2019年对全球公共卫生的十大威胁之一，与气候变化和抗菌素抗性相当，也是列表中仅有的三种传染病之一。世界一半的人口有登革热病毒感染的风险，主要是在低收入和中等收入国家。登革热疾病通常表现为热潮综合征，但在某些患者中，疾病发展为严重的阶段，出现了一般性和急性血液以及血管的液体渗漏，可能导致全身性休克和死亡。由于目前不适合在所有情况下使用的疫苗，没有特定的抗病毒药物，也没有预后的标志物来识别将会发展为严重疾病的患者，因此登革热为受影响的国家和个体带来了巨大的健康，经济和社会负担。实际上，肝功能障碍的生物标志物与登革热疾病的严重程度和预后不良相关。严重的登革热疾病影响肝脏，尤其是其脉管系统的方式，在机械水平上尚未完全理解，并且可能会提供重要的线索，以识别患有高风险患者患严重疾病的患者，以及开发药物以改善患者结果的新方法。该项目将着重于理解严重登革热患者肝脏中血管故障的发展，以专注于受登革热出血影响的血管的生物学。肝血管由两种细胞类型组成，即围绕着内皮管的血管内表面和血管周内表面（肝脏星状细胞）的内皮细胞。周细胞的功能是密切调节内皮细胞的功能并调节血管的完整性。我们自己的研究首次表明，病毒蛋白的存在称为“ NS1”，该病毒蛋白在严重的登革热患者的血液中以高浓度存在，可防止周细胞进行这种调节功能。确实，我们的实验表明，NS1蛋白会破坏内皮细胞和周细胞之间的相互作用，使内皮血管裸露而漏水，因为它们缺乏周细胞。 In this grant, we propose to study three separate ways in which dengue virus might be causing the dysfunction of liver hepatic stellate cells, and therefore provoking vessel leakage: (1) the impact of the NS1 protein present in patient blood, (2) direct infection of hepatic stellate cells by dengue virus, and (3) the release of inflammatory substances by infected liver cells (hepatocytes).在研究这些机制时，我们将重点关注它们如何通过导致其分化为不同细胞类型的肝星状细胞的身份，以及它们如何改变肝脏星状细胞与血管的关系，从而影响血管屏障的完整性。此外，我们将研究所有四种登革热病毒（血清型）的行为，因为据报道，严重症状的表现取决于每次暴发的主要变体。