Innate Immune Responses to Type 3 Secretion System Components and Effectors

描述(由申请人提供)：铜绿假单胞菌是一种机会人类病原体，能够引起急性感染，如呼吸机相关肺炎，以及呼吸道的慢性定植和感染。无论是在人类患者中还是在相应的哺乳动物感染模型中，铜绿假单胞菌的急性感染通常进展迅速；因此，天然免疫反应在控制这种病原体方面发挥重要作用也就不足为奇了。许多铜绿假单胞菌分子可触发宿主的先天免疫反应。反过来，在这种病原体感染期间，多个宿主途径能够做出反应。这种复杂性可以通过在体外研究特定细胞群体对铜绿假单胞菌的反应来降低；接下来的挑战在于了解这些反应是否以及如何在完整宿主中起到致病作用。在这一应用中，我们关注影响铜绿假单胞菌如何被天然免疫系统识别的细菌分子，这些分子触发的信号通路，以及细菌效应器对这些信号的修改。通过进行这些实验，我们将显着增加我们对宿主-病原体相互作用如何塑造肺部对铜绿假单胞菌的免疫反应的理解。这些信息是开发成功的免疫调节策略治疗急性或慢性铜绿假单胞菌感染的第一步。 公共卫生相关性：对感染细菌做出快速反应的能力可以保护大多数人免受铜绿假单胞菌引起的肺炎。在这一应用中，我们研究了负责识别细菌以产生这种保护性反应的免疫途径。然后我们问细菌毒素是如何中断这种快速免疫反应的。

DESCRIPTION (provided by applicant): Pseudomonas aeruginosa is an opportunistic human pathogen capable of causing both acute infections, such as ventilator-associated pneumonia, as well as chronic colonization and infection of the respiratory tract. Acute infections with P. aeruginosa usually progress rapidly, both in human patients and in corresponding mammalian infection models; thus, it is not surprising that innate immune responses play a significant role in controlling this pathogen. Many P. aeruginosa molecules trigger host innate immune responses. In turn, multiple host pathways are capable of responding during infection by this pathogen. This complexity can be reduced by studying the responses of specific cell populations to P. aeruginosa in vitro; the challenge then lies in understanding whether and how these responses contribute to pathogenesis in an intact host. In this application we focus on bacterial molecules that influence how P. aeruginosa is recognized by the innate immune system, on the signaling pathways that are triggered by these molecules, and on the modification of these signals by bacterial effectors. By carrying out these experiments we will significantly increase our understanding of how host-pathogen interactions shape the immune response to P. aeruginosa in the lung. Such information is a first step to developing successful immunomodulatory strategies for the treatment of acute or chronic P. aeruginosa infections. PUBLIC HEALTH RELEVANCE: The ability to respond rapidly to infecting bacteria protects most individuals from developing pneumonia due to Pseudomonas aeruginosa. In this application we investigate the immune pathways that are responsible for recognizing bacteria to generate this protective response. We then ask how bacterial toxins can interrupt this rapid immune response.