Francisella tularensis invasion of human erythrocytes

描述（由申请人提供）：土拉菌弗朗西斯菌是最具传染性的生物体之一，因为吸入单一细菌可导致致命的疾病，称为土拉菌病。因此，它被疾病控制和预防中心归类为a类生物防御剂。许多开创性的研究表明，土拉菌在巨噬细胞内复制的能力是这种生物体在感染期间的一个特征。直到最近，我们才意识到与非巨噬细胞的相互作用在感染过程中也非常重要，因为这些细胞为免疫保护、增殖和其他未被探索的作用提供了一个生态位。尽管在土拉菌领域的大部分工作都集中在这种有机体的巨噬细胞内生物学上，但与其他细胞类型的相互作用尚未得到彻底的研究。使用体内和体外方法，我们提出了强有力的证据，土拉菌侵入并持续存在于红细胞中。提出的工作将提供一个以前未被描述的现象的理解一类生物防御剂-即土拉菌的红细胞入侵。研究土拉菌侵染红细胞的两个目的是：

DESCRIPTION (provided by applicant): Francisella tularensis is one of the most infectious organisms as inhalation of a single bacterium can lead to a fatal disease referred to as tularemia. It has therefore been categorized by the Centers for Disease Control and Prevention as a Category A biodefense agent. Many seminal studies have shown that the ability of F. tularensis to replicate within macrophages is a feature of this organism during infection. Only recently we have appreciated that interactions with non-macrophages are also extremely important during infection as these cells provide a niche for immune protection, proliferation, and other unexplored roles. Although much of the work in the field of F. tularensis has focused on the intra-macrophage biology of this organism, interactions with other cell types have not been thoroughly investigated. Using both in vivo and in vitro approaches, we present strong evidence that F. tularensis invades and persists in erythrocytes. The proposed work will provide an understanding of a previously uncharacterized phenomenon by a Category A biodefense agent - namely erythrocyte invasion by F. tularensis. The two aims to investigate erythrocyte invasion by F. tularensis are: 1) To examine the molecular mechanism of F. tularensis erythrocyte invasion. 2) To determine the role of erythrocyte invasion by F. tularensis. As erythrocyte invasion of F. tularensis has not yet been described in the literature, the studies proposed here will open up a new line of research. We will investigate a potential role in pathogenesis, arthropod transmission, and disease persistence. Our work will involve evaluation of fixed blood from tularemia patients to assess the degree of erythrocyte invasion during human infection. We will also examine the mechanism by which F. tularensis erythrocyte invasion occurs, exposing novel host-microbe molecular pathways. In addition to enhancing our understanding of an important Category A biodefense agent, the research proposed may also uncover general systems implemented by diverse intracellular pathogens. The bacterial pathogen Francisella tularensis is a signficant bioterror threat. The research descibed in this proposal will make important advances toward understanding how this organism invades red blood cells. The results of this work may lead to vaccine development and potential therapeutics that alter the Francisella- erythrocytre interactions.