Aspergillus Angioinvasion and Dissemination

描述（由申请人提供）：烟曲霉引起的侵袭性感染正在增加，尽管有新的治疗方法，但死亡率仍高于50%。血管浸润是侵袭性曲霉病的一个标志性病理特征，在局部和播散性疾病的发展中起着关键作用。这种血管入侵和随后的传播过程是烟曲霉和少数其他致病霉菌所特有的，其机制尚不清楚。组织病理学研究表明，生物体进入和随后退出血管系统有几个关键步骤。首先，来自感染病灶的菌丝必须侵入血管的腔面，穿透内皮细胞进入血管腔。接下来，菌丝片段由血流携带到远端部位，在那里它们粘附并穿透血管内皮细胞的管腔表面，从而侵入深部器官。我们的总体假设是烟曲霉与血管内皮的相互作用是侵袭性曲霉病发病的关键。我们建议通过建立体外培养系统来研究烟曲霉与内皮细胞腔壁和腔壁的相互作用，从而研究其血管侵袭和血液播散的机制。利用该系统，我们将研究当菌丝感染内皮细胞的管腔表面和管腔表面时内皮细胞侵袭、刺激和损伤的机制。我们还将描述控制烟曲霉菌丝对内皮和亚内皮基质蛋白的腔内粘附的参数。最后，我们将用两种新的侵袭性肺曲霉病和血液播散性曲霉病小鼠模型验证我们的体外结果。这些研究旨在为烟曲霉入侵血管和血源性传播的分子机制的全面研究奠定基础。

DESCRIPTION (provided by the applicant): Invasive infections due to Aspergillus fumigatus are increasing, and despite new therapies are associated with greater than 50% mortality. Invasion of blood vessels is a hallmark pathologic feature of invasive aspergillosis and plays a critical role in the development of local and disseminated disease. This process of angioinvasion and subsequent dissemination is unique to A. fumigatus and a handful of other pathogenic molds, and its mechanism is not well understood. Histopathologic studies suggest that there are several key steps by which the organism gains entry to and subsequently exits from the vascular system. First, hyphae from an infectious focus must invade the abluminal surface of the blood vessel, and penetrate endothelial cells to gain access to the blood vessel lumen. Next, hyphal fragments are borne by the bloodstream to distal sites where they adhere to and penetrate the luminal surface of the endothelial cells lining the blood vessel and thereby invade the deep organs. Our overall hypothesis is that the interactions of A. fumigatus with the vascular endothelium are critical to the pathogenesis of invasive aspergillosis. We propose to study the mechanisms underlying angioinvasion and hematogenous dissemination by first developing an in vitro culture system that will enable us to study the interactions of A. fumigatus with both the abluminal and luminal surfaces of the endothelial cell. Using this system, we will investigate the mechanisms of endothelial cell invasion, stimulation, and injury when hyphae infect the abluminal vs. luminal surfaces of the endothelial cell. We will also characterize the parameters that govern the luminal adherence of A. fumigatus hyphae to endothelium and subendothelial matrix proteins. Finally, we will validate our in vitro results using two new murine models of invasive pulmonary and hematogenously disseminated aspergillosis. These studies are designed to lay the essential foundation for a comprehensive research program aimed at elucidating the molecular mechanisms by which A. fumigatus invades blood vessels and hematogenously disseminates.