Outer membrane lipoproteins of Borrelia burgdorferi

描述（由申请人提供）：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、心脏、神经和风湿病表现。美国每年报告的莱姆病病例超过1.5万例，一种安全有效的预防莱姆病疫苗已成为公共卫生的优先事项。在这方面，许多研究表明，该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）已被证明可以保护动物和人类免受伯氏疏螺旋体的感染，并在几年前被批准用于人类。然而，最近的事件导致OspA疫苗被撤出市场，现在不再向公众提供。因此，伯氏疏螺旋体研究的重点是开发一种新的疫苗，作为安全有效的第二代预防莱姆病的疫苗。由于伯氏疏螺旋体是一种细胞外病原体，而体液免疫已被证明对这种生物体具有保护作用，因此疫苗研究一直围绕着确定一种疏螺旋体抗原(i)表面暴露，（ii）在不同的螺旋体菌株和基因种中保守，以及（iii）在蜱虫传播和哺乳动物感染期间表达。我们最近使用微阵列实验来帮助鉴定新的候选疫苗分子，我们已经在初步研究中显示表面暴露，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，在体外培养过程中，针对这三种抗原产生的抗体都可以杀死伯氏疏螺旋体。因此，这项重点应用的主要目标是通过以下方法进一步表征这些表面暴露蛋白：(i)确定它们在伯氏疏螺旋体整个地方性动物生命周期中的细胞位置，（ii）检查它们在伯氏疏螺旋体不同菌株和基因种之间的总体遗传保护性，以及（iii）评估它们保护小鼠和非人灵长类动物免受实验性莱姆病的能力。拟议的研究应该导致候选疫苗分子，可以进一步测试人类作为第二代莱姆病疫苗使用的安全性和有效性。

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.