Outer membrane lipoproteins of Borrelia burgdorferi

描述(申请人提供)：莱姆病，由节肢动物传播的伯氏疏螺旋体引起，是一种多系统疾病，可导致皮肤病、心脏病、神经病和风湿病。由于美国每年报告的病例超过1.5万例，安全有效的莱姆病疫苗已成为公共卫生的优先事项。在这方面，大量的研究表明，这种生物的外膜脂蛋白可以作为有效的疫苗试剂。事实上，外表面脂蛋白A(OspA)已经被证明可以保护动物和人类免受伯氏杆菌的感染，并在几年前被批准用于人类。然而，最近的事件导致OspA疫苗被从市场上撤下，现在公众不再可以获得这种疫苗。因此，伯氏杆菌研究的一个主要重点是开发一种新的疫苗，这种疫苗可以作为安全有效的第二代莱姆病预防药物。由于伯氏杆菌是一种胞外病原体，体液免疫已被证明对这种生物具有保护作用，因此疫苗研究围绕确定一种疏螺旋体抗原，这种抗原是(I)表面暴露的，(Ii)在不同的螺旋体菌株和基因种之间保存的，以及(Iii)在蜱虫传播和哺乳动物感染中表达的。我们最近使用微阵列实验来帮助识别新的候选疫苗分子，我们在初步研究中证明了这些分子是表面暴露的，命名为BbA36、BbA69和BbI42。支持这些抗原可能是第二代莱姆病疫苗原的事实是，针对这三种抗原产生的抗体在体外培养过程中都可以杀死伯氏杆菌。因此，这一重点应用的主要目标是通过(I)确定它们在伯氏杆菌地方性生活史中的细胞位置，(Ii)检查它们在不同菌株和不同基因种之间的总体遗传保守性，以及(Iii)评估它们保护小鼠和非人类灵长类动物免受实验性莱姆病的能力，从而进一步表征这些表面暴露的蛋白质。拟议的研究应该会导致候选疫苗分子，这些分子可以在人体上进一步测试安全性和有效性，作为第二代莱姆病疫苗使用。

DESCRIPTION (provided by applicant): Lyme disease, caused by the arthropod-borne spirochete Borrelia burgdorferi, is a multisystem disorder that can lead to dermatologic, cardiac, neurologic, and rheumatologic manifestations. With more than 15,000 cases reported in the United States every year, a safe and effective vaccine for preventing Lyme disease has become a public health priority. In this regard, numerous lines of investigation indicate that outer membrane lipoproteins of this organism can be used as effective vaccine reagents. In fact, outer surface lipoprotein A (OspA) has been shown to protect animals and humans from infection with B. burgdorferi, and was approved for use in humans several years ago. However, recent events have led to the OspA vaccine being taken off the market and it is now no longer available to the general public. Therefore, a major emphasis in B. burgdorferi research has been to develop a new vaccine that could be used as a safe and effective second-generation preventative against Lyme disease. Since B. burgdorferi is an extracellular pathogen, and humoral immunity has been shown to be protective against this organism, vaccine studies have revolved around identifying a borrelial antigen that is (i) surface-exposed, (ii) conserved among different strains and genospecies of Borrelia spirochetes, and (iii) expressed during tick transmission and mammalian infection. We recently used microarray experiments to help identify new candidate vaccine molecules that we have shown to be surface-exposed in preliminary studies, designated BbA36, BbA69, and BbI42. Supporting the fact that these antigens may be possible 2nd generation Lyme disease vaccinogens is the fact that antibodies generated against all three can kill B. burgdorferi during in vitro cultivation. Therefore, the major goal of this focused application is to further characterize these surface-exposed proteins by (i) determining their cellular location throughout the enzootic life-cycle of B. burgdorferi, (ii) examining their overall genetic conservation among different strains and genospecies of B. burgdorferi, and (iii) assessing their ability to protect mice and non-human primates from experimental Lyme disease. The proposed studies should lead to candidate vaccine molecules that can be further tested for safety and efficacy in humans for use as a second- generation Lyme disease vaccine.