Genetics of Host Resistance to Chlamydia trachomatis

描述（由申请人提供）：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病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道路。对于提议的基因实验，我们决定集中在小鼠感染人类病原体沙眼衣原体。它是流行地区致盲的主要原因，可能是世界上细菌性传播疾病的最常见来源。根据对人类和动物衣原体感染的研究结果，似乎至少有一些疾病症状的差异可能是由于宿主对衣原体疾病不同成分易感性的遗传差异造成的。因此，我们希望利用人类衣原体疾病的小鼠模型，研究宿主遗传背景在衣原体感染严重程度中的作用。对于我们的第一个目标，我们将利用小鼠遗传学作为一种手段来完善影响沙眼衣原体急性全身感染结果的数量性状位点（QTL）的位置，该位点旨在模拟称为性病淋巴粒的人类性传播疾病的要素。对于第二个目标，我们将确定那些QTL影响的基因。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。

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.