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的伯氏疏螺旋体（Bb）引起的多系统疾病，是美国最常见的病媒传播疾病。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。哺乳动物先天性免疫细胞通过模式识别受体的Toll样受体家族对促炎性Bb脂蛋白做出反应，所有这些受体都利用共同的衔接蛋白MyD 88来启动炎症。MyD 88缺陷型小鼠感染Bb后，在面对强烈的体液免疫应答时表现出不受控制的病原体生长，但发展出与野生型小鼠相同的疾病。该提案将使用MyD 88缺陷小鼠来检查先天免疫性在蜱获得和传播高和低感染性Bb基因型中的作用，以及相对于感染螺旋体基因型的小鼠中疾病的演变。使用蜱的异种诊断以前曾被用于记录抗生素治疗B b感染小鼠后减毒螺旋体的持续存在，治疗后1年可在关节中发现螺旋体DNA。该提议的第二个目标是利用Bb感染的MyD 88缺陷小鼠的高病原体负荷，以1）促进在喂食用抗生素处理的Bb感染的小鼠后由异种诊断蜱回收的螺旋体的分子表征; 2）通过培养技术以及Bb基因表达微阵列确定关节中的残留DNA是否反映持久的活螺旋体;和3）评价组合口服抗生素方案在从感染关节中消除Bb DNA中的效用。这些研究的结果将增强我们对哺乳动物宿主因素的理解，这些因素有助于感染和疾病的易感性，并可能允许鉴定宿主适应性螺旋体表达的基因，这些基因可用于建立诊断和/或抗生素治疗的疗效。

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.