Francisella tularensis invasion of human erythrocytes

描述（由申请方提供）：土拉热弗朗西丝菌是最具传染性的微生物之一，因为吸入单一细菌可导致致命性疾病（称为土拉菌病）。因此，它已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，F。土拉热菌在巨噬细胞内复制是该生物体在感染期间的特征。直到最近，我们才意识到与非巨噬细胞的相互作用在感染期间也非常重要，因为这些细胞为免疫保护，增殖和其他未探索的作用提供了一个利基。虽然F.土拉热主要集中在这种生物体的巨噬细胞内生物学，与其他细胞类型的相互作用尚未得到彻底研究。使用体内和体外的方法，我们提出了强有力的证据，F。土拉菌侵入并持续存在于红细胞中。拟议的工作将提供一个以前未表征的现象，由A类生物防御剂的理解-即红细胞入侵的F。土拉热。这两个目的是研究F.土拉热是： 1)探讨F.土拉热红细胞侵入。 2)探讨F.土拉热。 随着红细胞侵入F.土拉热尚未在文献中描述，这里提出的研究将开辟一条新的研究路线。我们将调查在发病机制，节肢动物传播和疾病的持久性的潜在作用。我们的工作将涉及评价兔热病患者的固定血液，以评估人类感染期间红细胞侵入的程度。我们还将研究F.土拉菌红细胞侵入发生，暴露了新的宿主-微生物分子途径。除了增强我们对一种重要的A类生物防御剂的理解外，这项研究还可能揭示由不同细胞内病原体实施的一般系统。 土拉热弗朗西斯菌是一种严重的生物恐怖威胁。该提案中描述的研究将在了解这种生物体如何侵入红细胞方面取得重要进展。这项工作的结果可能导致疫苗的开发和潜在的治疗方法，改变弗朗西斯菌-红细胞相互作用。

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.