HOST RESPONSES TO THE TULAREMIA AGENT

人兔热病是一种高致病力的细菌性人畜共患病，在北方具有地方性疫源地。 其临床表现取决于感染途径。 溃疡腺型是处理土拉弗朗西斯菌污染源后最常见的表现。 当摄入受污染的食物或水时，可引起口咽形式。 肺、伤寒（实验室工作者报告的两种较常见的形式）、腺和眼形式是其他较不常见的表现。 该病以暴发形式发生，通常与直接接触受感染的野味或受污染的水有关，或在节肢动物传播的兔热病中以季节性模式发生。这种感染的严重性，其最初的非特异性表现，以及该因子在环境中生存的能力，导致了F。土拉热菌被列入可用于生物恐怖主义的细菌病原体名单。人和小鼠对F.土拉热已经被研究，特别强调细菌在巨噬细胞内的存活和由细胞内感染引起的细胞因子应答。 不太清楚的是这种生物体与细胞的相互作用，它必须遇到引起全身感染。 因此，对F.具有内皮的土拉热菌被提议用于该R03应用。弱毒疫苗株和强毒美国株（F. tularensis tularensis）将用于内皮感染及其促炎活化的平行实验，如通过粘附分子和趋化因子表达的上调所测量的。 土拉菌病的一个特征尚未被研究，即这种生物体在受感染宿主体内的传播方式。 兔热病的病变含有明显的单核细胞浸润，病变形成的顺序尚不清楚。 将通过评估细菌和细菌感染的细胞（中性粒细胞、单核细胞）在体外穿过内皮的能力来研究细菌单独和感染细胞的运输。早期的研究发现，F.土拉热菌不激活单核细胞，因此其对内皮细胞刺激的作用尚不清楚，也不确定对脂多糖或整个生物体的应答存在CD 14依赖性。 这项研究的目的是为了更好地了解F。土拉菌引起全身感染。

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.