Causes and consequences of ospC variation in Borrelia burgdorferi to Lyme disease

伯氏疏螺旋体 ospC 变异导致莱姆病的原因和后果

• 批准号: 7350431
• 负责人: Dustin Brisson
• 金额: $ 34.83万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-15 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7350431
• 关键词: Address; Affect; Affinity; Amino Acid Sequence; Animals; Area; Arthropods; Bacteria; Binding; Biological; Biology; Borrelia burgdorferi; Communities; Data; Disease; Ecology; Emerging Communicable Diseases; Endopeptidases; Epidemic; Evolution; Genetic; Genetic Polymorphism; Genotype; Goals; Health; Human; Incidence; Insecta; Intervention; Invasive; Laboratories; Lead; Lyme Disease; Modeling; Molecular; Nature; Order Spirochaetales; Organism; OspC protein; Patients; Peptide Hydrolases; Plasminogen; Play; Population; Predisposition; Process; Public Health; Range; Relative (related person); Role; Serine Protease; Solid; Solutions; Structure; Testing; Ticks; Vaccines; Variant; Vector-transmitted infectious disease; Work; base; density; design; disorder risk; feeding; feral; insight; pathogen; preference; transmission process; vaccine development

DESCRIPTION (provided by applicant): Diseases transmitted from animals to humans are the most prevalent type of emerging infectious disease threatening human health. Lyme disease, caused by the bacterium Borrelia burgdorferi, affects more people than any other arthropod-borne (carried by insects or ticks) disease in the US. However, humans cannot be infected by all B. burgdorferi strains; the infectiousness in humans is strongly correlated with the genetic sequence at the outer surface protein C (ospC) locus of the bacteria. Of the 15 OspC variants found in the Northeastern US, only 5 are represented among strains isolated from Lyme disease patients. Similarly, each feral vertebrate species transmits a unique subset of genotypically distinct strains (ospC genotypes) to feeding ticks. That is, each vertebrate species in nature acts as a unique ecological niche that is infected with, and amplifies (transmits to feeding ticks), a different subset of the 15 ospC genotypes. Thus, the abundance of each genotype, including those that are infectious to humans, are determined by the composition and relative densities of vertebrate species. However the causal role of OspC in determining the vertebrate species a strain can infect has yet to be investigated. The major aim of this proposal is to determine if the variation in ability to infect vertebrate species, including humans, among genotypes is causally related to differences in OspC sequence. We will assess the causes and public health consequences of host selectivity of genotypes by integrating across three levels of biological complexity; molecular, organismal, and population - to address fundamental questions in Lyme disease ecology and evolution. Controlling the current Lyme disease epidemic via a human vaccine appears to be many years from actualization. Reducing the abundance of human-infectious ospC genotypes is an alternative, effective, and long-term solution to diminish Lyme disease incidence. However, intervention strategies to this end require a solid understanding of the basic biology of B. burgdorferi from the molecular to the population level. The long term goal of this proposal is to determine the mechanistic causes, both molecular and ecological, that contribute to human Lyme disease risk that could aid in the design of ecological control strategies or vaccine development. In the near term, these studies will lead to a mechanistic understanding of infectivity in vertebrate species; few examples are known of a functional basis determining the range of animal hosts a pathogen species can infect. From a global disease ecology perspective, this work is relevant as within population polymorphisms maintained by host species selectivity may be a prominent feature of the ecology of many emerging infectious diseases. In the near term, these studies will furnish fundamental new insights into factors affecting the natural abundance of, and disease risk from, animal-transmitted pathogens. Lyme disease is the most prevalent insect or tick transmitted disease in the US. Yet we know little about the mechanisms that contribute to invasiveness in humans or that escalate human Lyme disease risk. The long term goal of this proposal is to determine the mechanistic causes, both molecular and ecological, that contribute to human Lyme disease risk that could aid in the design of ecological control strategies or vaccine development.

描述（由申请人提供）：由动物传播给人类的疾病是威胁人类健康的最常见的新发传染病类型。莱姆病由伯氏疏螺旋体引起，在美国比任何其他节肢动物传播（由昆虫或蜱虫传播）的疾病影响更多的人。但是，人类不可能被所有的B感染。burgdorferi菌株;对人类的感染性与细菌外表面蛋白C（ospC）基因座的遗传序列密切相关。在美国东北部发现的15种OspC变体中，只有5种在从莱姆病患者分离的菌株中有代表性。类似地，每种野生脊椎动物物种将基因型不同的菌株（ospC基因型）的独特子集传递给取食蜱。也就是说，自然界中的每种脊椎动物物种都是一个独特的生态位，它感染并放大（传播给喂食蜱）15种ospC基因型的不同子集。因此，每种基因型的丰度，包括那些对人类有感染性的基因型，是由脊椎动物物种的组成和相对密度决定的。然而，OspC在确定菌株可以感染的脊椎动物物种中的因果作用还有待研究。该建议的主要目的是确定基因型之间感染脊椎动物物种（包括人类）的能力的变化是否与OspC序列的差异有因果关系。我们将通过整合生物复杂性的三个层次来评估基因型宿主选择性的原因和公共卫生后果;分子，生物体和人口-以解决莱姆病生态学和进化中的基本问题。通过人类疫苗控制目前的莱姆病流行似乎还需要很多年才能实现。减少人类感染性ospC基因型的丰度是减少莱姆病发病率的替代、有效和长期的解决方案。然而，为此目的的干预策略需要对B的基本生物学有扎实的理解。从分子水平到种群水平。该提案的长期目标是确定导致人类莱姆病风险的分子和生态机制原因，这可能有助于设计生态控制策略或疫苗开发。在短期内，这些研究将导致脊椎动物物种的感染性的机制的理解，很少有例子是已知的功能基础确定的范围内的动物宿主的病原体物种可以感染。从全球疾病生态学的角度来看，这项工作是相关的，因为宿主物种选择性维持的种群多态性可能是许多新出现的传染病生态学的一个突出特征。在短期内，这些研究将为影响动物传播病原体的自然丰度和疾病风险的因素提供基本的新见解。莱姆病是美国最流行的昆虫或蜱传播疾病。然而，我们对导致人类入侵或加剧人类莱姆病风险的机制知之甚少。该提案的长期目标是确定导致人类莱姆病风险的分子和生态机制原因，这可能有助于设计生态控制策略或疫苗开发。