Innate Immunity in Vector-Borne Lyme Borreliosis

描述（由申请人提供）：莱姆病是一种由蜱传播螺旋体伯氏疏螺旋体（Bb）引起的多系统疾病，是美国最常见的媒介传播疾病。影响感染结果的因素包括感染螺旋体的基因型、宿主免疫反应和抗生素的使用。哺乳动物先天免疫细胞通过toll样受体家族的模式识别受体对促炎Bb脂蛋白作出反应，所有这些受体都利用共同的接驳蛋白MyD88来启动炎症。感染Bb的myd88缺陷小鼠在面对强烈的体液免疫反应时表现出不受控制的病原体生长，但发展成与野生型小鼠相同的疾病。本研究将利用myd88缺陷小鼠研究先天免疫在蜱虫获得和传播高、低传染性Bb基因型中的作用，以及相对于感染螺旋体基因型小鼠的疾病进化。以前曾使用蜱虫异种诊断来记录bb感染小鼠在抗生素治疗后减毒螺旋体的持久性，并且在治疗后长达1年的关节中可以发现螺旋体DNA。本研究的第二个目标是利用bb感染的myd88缺陷小鼠的高病原体负担，以1)促进对螺旋体的分子表征，这些螺旋体是由异诊断蜱在喂食抗生素治疗的bb感染小鼠后获得的；2)通过培养技术和Bb基因表达微阵列检测关节残留DNA是否反映了持续性活螺旋体；3)评估联合口服抗生素方案在消除感染关节Bb DNA方面的效用。这些研究的结果将增强我们对导致感染和疾病易感性的哺乳动物宿主因素的理解，并可能允许鉴定宿主适应螺旋体表达的基因，这些基因可用于建立诊断和/或抗生素治疗的有效性。

DESCRIPTION (provided by applicant): Lyme disease, a multisystem disorder due to the tick-transmitted spirochete Borrelia burgdorferi (Bb), is the most common vector-borne disease in the United States. Factors that influence the outcome from infection include genotype of the infecting spirochete, host immune responses, and use of antibiotics. Mammalian innate immune cells respond to proinflammatory Bb lipoproteins through tile Toll-like receptor family of pattern recognition receptors, all of which utilize the common adaptor protein MyD88 to initiate inflammation. MyD88-deficient mice infected with Bb exhibit uncontrolled pathogen growth in the face of strong humoral immune responses, yet develop disease identical to that seen in wild-type mice. This proposal will use MyD88-deficient mice to examine the role of innate irmmunity in tick acquisition and transmission of high and low infectivity Bb genotypes and the evolution of disease in the mouse relative to infecting spirochete genotype. Xenodiagnosis using ticks has previously been used to document the persistence of attenuated spirochetes after antibiotic treatment of Bb-infected mice, and spirochete DNA can be found in the joints as much as 1 year after treatment. A second goal of this proposal is to exploit the high pathogen burden of Bb-infected MyD88-deficient mice to 1) facilitate the molecular characterization of spirochetes that are retrieved by xenodiagnostic ticks after feeding on Bb-infected mice treated with antibiotics; 2) determine whether residual DNA in joints reflects persistent viable spirochetes through culture techniques as well as Bb gene expression microarrays; and 3) evaluate the utility of a combination oral antibiotic regimen in the elimination of Bb DNA from infected joints. The results of these studies will enhance our understanding of mammalian host factors that contribute to susceptibility to infection and disease, and may permit the identification of genes expressed by host-adapted spirochetes that can be used for establishment of diagnosis and/or efficacy of antibiotic therapy.