Genetics of Host Resistance to Chlamydia trachomatis

描述(申请人提供)：宿主遗传变异在感染结果中起很大作用。因此，对传染病抗性的遗传分析可以揭示影响疾病进程严重程度的重要基因。这种类型的基因分析在小鼠的各种感染模型中都非常成功，这些数据为可能影响人类感染的候选基因指明了方向。对于拟议的基因实验，我们决定将重点放在感染人类病原体沙眼衣原体的小鼠身上。它是流行地区失明的主要原因，也可能是世界上细菌性传播疾病的最常见来源。根据对人类和动物感染衣原体的研究结果，似乎至少有一部分疾病症状的差异是由于宿主对衣原体疾病不同因素的易感性存在遗传差异。因此，我们希望使用一种人类衣原体疾病的小鼠模型来研究宿主遗传背景在衣原体感染严重程度中的作用。为了我们的第一个目标，我们将利用小鼠遗传学作为一种手段来精炼数量性状基因座(QTL)的位置，该QTL影响沙眼衣原体急性系统性感染的结果，这种沙眼衣原体旨在模拟人类性传播疾病的元素，称为性淋巴颗粒菌。对于第二个目标，我们将确定那些QTL效应的基础基因。对于第三个目标，我们将研究前两个目标中分离的基因，以确定它们对细胞内细菌复制的影响。 该项目将尝试定义影响沙眼衣原体感染引起的疾病易感性的小鼠基因。人类很可能会有相似的基因功能，从而影响对传染病的相似易感性。由于沙眼衣原体感染在人类人群中很常见，了解这些基因可能有助于设计这种感染的诊断或治疗方法。

DESCRIPTION (provided by applicant): Host genetic variation plays a large role in the outcome of infection. Therefore, genetic analysis of resistance to infectious disease can reveal genes important for affecting the severity of disease course. This type of genetic analysis has been very successful in the mouse for a variety of infection models, and this data has pointed the way to candidate genes that could affect human infections. For the proposed genetic experiments, we have decided to focus on mouse infections with the human pathogen Chlamydia trachomatis. It is a major cause of blindness in endemic regions, and may be the most common source of bacterial sexually transmitted disease in the world. Based on the results of studies of human and animal infections with Chlamydia, it seems likely that at least some of the variations in disease symptoms result from genetic differences in host susceptibility to distinct elements of chlamydial disease. Therefore, we want to study the role of host genetic background in the severity of Chlamydia infections, using a mouse model of a human chlamydial disease. For our first Aim, we will utilize mouse genetics as a means to refine the location of Quantitative Trait Loci (QTL) that influence the outcome of an acute systemic infection with C. trachomatis, which is designed to model elements of the human sexually transmitted disease called lymphogranulum venereum. For the second Aim, we will identify the genes that underlie the effects of those QTL. For the third Aim, we will study the genes isolated in the first 2 Aims, to determine their effects on intracellular bacterial replication. This project will attempt to define mouse genes that affect susceptibility to disease caused by infections with Chlamydia trachomatis. It is likely that humans will have similar gene functions that will influence similar susceptibilities to infectious disease. Since infections with Chlamydia trachomatis are common in the human population, it is possible that knowledge of these genes could help to design diagnostics or therapies for this infection.