Haemophilus ducreyi Inhibits Phagocytosis

杜克雷嗜血杆菌抑制吞噬作用

• 批准号: 8266019
• 负责人: Eric John Hansen
• 金额: $ 39.68万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-01-01 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8266019
• 关键词: Affect; Animals; Bacteria; Cloning; Communicable Diseases; Data; Defense Mechanisms; Development; Disease; Elements; Experimental Models; Family; Genes; Genital system; Gram-Negative Bacteria; Hemophilus ducreyi; Host Defense; Host Defense Mechanism; Human; Human body; In Vitro; Instruction; Knowledge; Lesion; Liquid substance; Phagocytes; Phagocytosis; Phagocytosis Inhibition; Production; Protein Tyrosine Kinase; Proteins; Public Health; Recombinants; Research; Research Project Grants; Role; Signal Pathway; Signal Transduction; Ulcer; Virulence; killings; macrophage; mutant; paralogous gene; prevent; research study

Haemophilus ducreyi is the etiologic agent of chancroid, a sexually transmitted genital ulcer disease. Very little Is known about how this unencapsulated. Gram-negative bacterium evades host defenses and causes demrial lesion development. However, it has been shown that H. ducreyi has the ability to prevent phagocytosis of both itself and secondary targets by macrophages in vitro. We identified two extremely large H. ducreyi proteins, designated LspA1 and LspA2, that are released into H. ducreyi culture supernatant fluid and which are necessary for the observed inhibition of phagocytic activity. That these proteins are relevant to disease production was proven by the finding that a H. ducreyi mutant unable to express either LspA1 or LspA2 had drastically reduced virulence in both animal and human models of experimental chancroid. Little is known, however, about how the LspA proteins inhibit phagocytic activity. The proposed research project in this MERIT extension application will investigate the stoicture, function, and expression of the LspA proteins. In the first Specific Aim, we will capitalize on our recent successful cloning of the H. ducreyi IspAl gene to purify a functional recombinant LspAl protein and then determine the composition of the active form of this protein. In the second Specific Aim, we will elucidate the mechanism of action involved in the inhibition of phagocytic activity by the LspA proteins. We already have data which indicate that the LspA proteins can affect signaling pathways that control phagocytosis in macrophages, and our research efforts will be focused on the most proximal elements, and especially the Src family protein tyrosine kinases, in the phagocytic signaling cascade. In the third Specific Aim, we will characterize the H. ducreyi CpxRA two-component signal transduction system that is responsible for control of expression of both the LspA proteins as well as other co-regulated gene products of this bacterium. RELEVANCE (See instructions): The relevance of this research to public health involves the new infomnation that will be gained about H. ducreyi inhibits phagocytosis, one of the primary defense mechanisms of the human body. The ability of phagocytes to engulf and kill bacteria is essential to preventing or curing infectious diseases. Infomnation gained from this study will help us understand how phagocytes control this protective activity.

嗜血杆菌Ducreyi是一种性传播的生殖器溃疡疾病的病因学药。非常 关于这种未包容的方式知之甚少。革兰氏阴性细菌逃避了宿主的防御和原因 Demrial病变的发展。但是，已经表明H. ducreyi具有防止 巨噬细胞在体外对巨噬细胞的吞噬作用。我们确定了两个非常大的 H. ducreyi蛋白（指定的LSPA1和LSPA2）释放到H. ducreyi培养上清液中 这是观察到抑制吞噬活性所必需的。这些蛋白质是相关的 疾病产生的发现证明了杜克里菌突变体无法表达LSPA1或 LSPA2在实验性牙冠的动物和人类模型中的毒力大大降低。小的 然而，已经知道LSPA蛋白如何抑制吞噬活性。拟议的研究项目 在此功绩扩展应用程序中，应用程序将研究LSPA的隔离，功能和表达 蛋白质。在第一个具体目的中，我们将利用最近成功的H. ducreyi克隆 ISPAL基因纯化功能性重组LSPAL蛋白，然后确定 该蛋白的活性形式。在第二个特定目标中，我们将阐明涉及的作用机理 LSPA蛋白抑制吞噬活性。我们已经有数据表明 LSPA蛋白会影响控制巨噬细胞吞噬作用的信号通路，我们的研究 努力将集中在最近端的元素上，尤其是SRC家族蛋白酪氨酸激酶， 在吞噬信号传导级联中。在第三个特定目的中，我们将表征H. ducreyi cpxra 两个组件信号转导系统，负责控制两个LSPA的表达 该细菌的蛋白质以及其他共同调节的基因产物。 相关性（请参阅说明）： 这项研究与公共卫生的相关性涉及将获得有关H的新信息。 Ducreyi抑制吞噬作用，吞噬作用是人体的主要防御机制之一。能力 吞噬和杀死细菌的吞噬细胞对于预防或治愈传染病至关重要。秘诀 从这项研究中获得的将有助于我们了解吞噬细胞如何控制这种保护活动。