Haemophilus ducreyi Inhibits Phagocytosis

杜克雷嗜血杆菌抑制吞噬作用

• 批准号: 8082227
• 负责人: Eric John Hansen
• 金额: $ 14.05万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-07 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8082227
• 关键词: Affect; Animals; Bacteria; Chimeric Proteins; Communicable Diseases; Data; Defense Mechanisms; Dermal; Development; Disease; Experimental Models; Genital system; Gram-Negative Bacteria; Hemophilus ducreyi; Host Defense; Host Defense Mechanism; Human; Human body; In Vitro; Ingestion; Knowledge; Lesion; Liquid substance; Molecular; Phagocytes; Phagocytosis; Phagocytosis Inhibition; Production; Proteins; Public Health; Research; Research Project Grants; Signal Pathway; Structure; Ulcer; Virulence; in vivo; 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 dermal lesion development. However, it has been shown that H. ducreyi has the ability to resist phagocytosis in vivo. Moreover, this bacterium can prevent phagocytosis of both itself and secondary targets by macrophages in vitro. We have identified two extremely large H. ducreyi proteins, designated LspAt and LspA2, that are released into H. ducreyi culture supernatant fluid and which are responsible 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. Nothing is known, however, about how the LspA proteins inhibit phagocytic activity. The proposed research project is focused on the structure, function, and expression of the LspA proteins. In the first Specific Aim, we will purify either a functional LspAt fusion protein or native LspA1 protein and 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. In the third Specific Aim, we will identify the H. ducreyi gene products that are responsible for control of expression of the LspA proteins by this bacterium. The relevance of this research to public health involves the new information that will be gained about 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. Information gained from this study will help us understand how phagocytes control this protective activity.

杜克雷嗜血杆菌是软下疳的病原体，软下疳是一种性传播的生殖器溃疡疾病。非常 关于这种未被包裹的革兰氏阴性细菌如何逃避宿主防御并引起 皮肤病变发展。然而，已经表明H. ducreyi有能力抵抗 体内吞噬作用。此外，这种细菌可以防止吞噬本身和继发性 体外巨噬细胞的靶点。我们已经确定了两个非常大的H。ducreyi蛋白，命名为 LspAt和LspA2被释放到H. ducreyi培养上清液，并负责 观察到的吞噬活性抑制。这些蛋白质与疾病的产生有关， 证明了一个H.不能表达LspA1或LspA2的ducreyi突变体， 降低动物和人类实验性软下疳模型的毒力。然而，目前还不清楚， LspA蛋白是如何抑制吞噬细胞活性的拟议的研究项目的重点是 LspA蛋白的结构、功能和表达。在第一个具体目标中，我们将净化 功能性LspAt融合蛋白或天然LspA1蛋白，并确定LspA1的活性形式的组成， 这种蛋白质。在第二个具体目标中，我们将阐明参与的作用机制。 通过LspA蛋白抑制吞噬活性。我们已经有数据表明LspA 蛋白质可以影响控制巨噬细胞中吞噬作用的信号传导途径。在第三个具体目标中， 我们就能找到H负责控制LspA表达的ducreyi基因产物 这种细菌的蛋白质。 这项研究与公共卫生的相关性涉及将获得的新信息， 吞噬作用，人体的主要防御机制之一。吞噬细胞的能力 吞噬和杀死细菌对预防或治疗传染病至关重要。由此获得的信息 这项研究将帮助我们了解吞噬细胞如何控制这种保护活性。