Haemophilus ducreyi Inhibits Phagocytosis

杜热氏嗜血杆菌是一种性传播生殖器溃疡疾病--下巴的病原体。非常 关于这种无包膜的革兰氏阴性细菌是如何逃避宿主防御和引起的，人们知之甚少。 皮肤损伤的发展。然而，已有研究表明，杜克雷病毒具有抵抗能力。 体内的吞噬作用。此外，这种细菌还可以防止自身和继发性的吞噬。 巨噬细胞的体外靶点。我们已经鉴定出两个极大的杜氏杆菌蛋白，命名为 LspAt和LspA2，它们被释放到杜氏杆菌培养上清液中，负责 观察到吞噬活性的抑制。这些蛋白质与疾病的产生有关 发现一个既不能表达LspA1也不能表达LspA2的H.ducreyi突变体 降低了动物和人类模型的实验性下巴的毒力。然而，什么都不知道， LspA蛋白是如何抑制吞噬活性的。建议的研究项目主要集中在 LspA蛋白的结构、功能和表达。在第一个特定目标中，我们将净化一个 功能性LspAt融合蛋白或天然LspA1蛋白，并测定其活性形式的组成 这种蛋白质。在第二个具体目标中，我们将阐明 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吞噬作用的信号通路。在第三个具体目标中， 我们将鉴定负责控制LspA表达的杜氏杆菌基因产物 这种细菌产生的蛋白质。 这项研究与公共卫生的相关性涉及到将获得的关于 吞噬作用，人体的主要防御机制之一。吞噬细胞的能力 吞噬和杀灭细菌对于预防或治愈传染病是必不可少的。从这一点上获得的信息 研究将帮助我们了解吞噬细胞是如何控制这种保护活动的。

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.