HOST RESPONSES TO THE TULAREMIA AGENT

人图拉热病是一种高度致病的细菌性人畜共患病，在北半球有地方性疫源地。其临床表现取决于感染途径。在处理被图拉氏方济氏菌污染的污染源后，溃疡腺样形态是最常见的表现。当摄入受污染的食物或水时，可能会导致口咽形式。肺型、伤寒(实验室工作人员报告的两种较常见的类型)、腺型和眼型是其他较不常见的表现。这种疾病在暴发中发生，通常与直接接触受感染的猎物或受污染的水有关，或者在节肢动物传播的图拉热症中呈季节性模式。这种感染的严重性，其最初的非特异性表现，以及该病原体在环境中的生存能力，导致图拉氏丝虫被列入可用于生物恐怖主义的细菌病原体名单。已经研究了人类和小鼠对图拉氏杆菌的反应，特别是细菌在巨噬细胞内的存活和细胞内感染引起的细胞因子反应。鲜为人知的是这种有机体与细胞的相互作用，它必须遇到这些细胞才能引起全身感染。因此，对于R03的应用，建议对图拉氏丝菌与内皮细胞的相互作用进行非常集中的研究。通过上调黏附分子和趋化因子的表达，减毒疫苗毒株和美国毒株(F.tularensis tularensis)都将被用于内皮感染及其促炎活性的平行实验。图拉热症的一个特征尚未被研究，那就是这种微生物在受感染宿主内的传播方式。Tulareic病变含有明显的单核细胞浸润，病变形成的顺序尚不清楚。细菌本身和感染细菌的细胞(中性粒细胞、单核细胞)的运输将通过评估它们在体外穿越内皮的能力来研究。早期的研究发现，图拉氏狸殖吸虫的脂多糖不能激活单个核细胞，因此其对内皮细胞的刺激作用尚不清楚，也不确定是否存在对脂多糖或整个生物体的CD14依赖的反应。这项拟议的研究旨在更好地了解图拉氏丝虫引起全身感染的机制。

Human tularemia is a highly virulent bacterial zoonosis with endemic foci in the northern hemisphere. Its clinical manifestations depend on the route of infection. The ulceroglandular form is the most common presentation after handling sources contaminated with Francisella tularensis. When ingested, contaminated food or water can cause an oropharyngeal form. Pulmonary, typhoidal (the two more common forms reported in laboratory workers), glandular and ocular forms are other less frequent presentations. The disease occurs in outbreaks, usually associated with direct contact with infected game or contaminated water, or in a seasonal pattern in arthropod-borne tularemia. The severity of this infection, its initial nonspecific manifestations, and the ability of the agent to survive in the environment have led to the inclusion of F. tularensis in a list of bacterial pathogens that could be used for bioterrorism. The human and murine responses to F. tularensis have been studied with particular emphasis on the survival of the bacterium within macrophages and the cytokine responses resulting from intracellular infection. Less known are the interactions of this organism with cells that it must encounter to cause systemic infection. Thus, a very focused study of the interaction of F. tularensis with endothelium is proposed for this R03 application. Both the attenuated vaccine strain and the virulent American strain (F. tularensis tularensis) will be used for parallel experiments on infection of endothelium and its pro-inflammatory activation, as measured by upregulation of expression of adhesion molecules and chemokines. One feature of tularemia that has not been investigated is the manner of spread of this organism within the infected host. Tularemic lesions contain a marked mononuclear cell infiltrate, and the sequence of lesion formation is not known. Trafficking of the bacterium alone and of cells infected with the bacterium (neutrophils, monocytes) will be studied by assessing their ability to cross endothelium in vitro. Earlier studies have found that the lipopolysaccharide of F. tularensis does not activate mononuclear cells, so its effect on stimulation of endothelial cells is not clear, nor is there a certainty that there is a CD14-dependency of the response to the lipopolysaccharide or the whole organism. The proposed research is aimed at a greater understanding of the mechanisms used by F. tularensis to cause systemic infection.