Decorin-binding proteins of Borrelia burgdorferi

淋巴疾病仍然是一个主要的公共卫生问题，莱姆病的许多方面 因此，发病机制和免疫学值得进一步研究。核心蛋白结合蛋白A(DbpA)，a 伯氏疏螺旋体的膜脂蛋白参与了伯氏疏螺旋体的寄生策略。 在哺乳动物组织入侵过程中，伯氏杆菌发挥细胞基质结合粘附素的作用。DbpA也 已经成为最突出的新人类莱姆病疫苗候选。但是，的许多功能 DbpA的时间表达、膜拓扑结构、在伯氏杆菌毒力中的作用以及总体上 作为一种保护性免疫原的效用仍然知之甚少。目前的研究解决了这些重要的问题 信息鸿沟。为此，本提案的具体目的是：(1)审查时间 蜱传伯氏杆菌DbpA在哺乳动物(小鼠)宿主中的表达模式(S)，(2)到 在哺乳动物中检测由壁虱传播的伯氏杆菌表达的DbpA的膜拓扑结构 (小鼠)宿主，(3)通过插入失活构建强毒伯氏杆菌DbpA缺陷突变体 DbpA的表达，重点研究了DbpA在伯氏杆菌感染性、毒力、 和疾病的发病机制，以及(4)进一步检验DbpA作为疫苗原在 莱姆型疏螺旋体病小鼠模型。关于后者，重点将放在(A)净化上 重组DbpA(作为免疫原)以保持其天然构象和(B)扁虱感染(挑战 模拟伯氏杆菌自然传播的DbpA免疫小鼠的途径。这个 目前的建议是对DbpA在莱姆病发病机制中的作用进行全面研究 疾病及其作为人类莱姆病疫苗的潜力。

Lymc disease continues to represent a major public health problem, and many aspects of Lyme disease pathogenesis and immunology thus warrant further investigation. Decorin-binding protein A (DbpA), a membrane lipoprotein of Borrelia burgdorferi, has been implicated in subserving the parasitic strategy of B. burgdorferi by functioning as a cell matrix-binding adhesin during mammalian tissue invasion. DbpA also has emerged as the most prominent new human Lyme disease vaccine candidate. However, many features of DbpA, such as its temporal expression, membrane topology, role in B. burgdorferi virulence, and overall utility as a protective immunogen, remain poorly understood. The current study addresses these important information gaps. To this end, the Specific Aims of this proposal are: (1) To examine the temporal expression pattern(s) of DbpA by tick-transmitted B. burgdorferi in the mammalian (mouse) host, (2) To examine the membrane topology of DbpA expressed by tick-transmitted B. burgdorferi in the mammalian (mouse) host, (3) To construct a DbpA-deficient mutant of virulent B. burgdorferi by insertional inactivation of dbpA, with emphasis on examining the role of DbpA expression in B. burgdorferi infectivity, virulence, and disease pathogenesis, and (4) To examine further the overall efficacy of DbpA as a vaccinogen in the mouse model of Lyme borreliosis. Regarding the latter, emphasis will be placed on (a) purifying recombinant DbpA (as immunogen) to preserve its native conformation and (b) tick infestation (challenge route for B. burgdorferi) of DbpA-immunized mice to mimic natural B. burgdorferi transmission. The current proposal represents a comprehensive study of the role of DbpA in both the pathogenesis of Lyme disease and its potential as a human Lyme disease vaccine.