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

描述(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。莱姆病是由伯氏疏螺旋体细菌引起的，在美国比任何其他节肢动物传播的(由昆虫或扁虱传播的)疾病影响更多的人。然而，人类不可能感染所有的伯氏杆菌菌株；人类的传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个OspC变种中，只有5个出现在莱姆病患者分离的菌株中。类似地，每个野生脊椎动物物种都会将一组独特的、具有不同基因特征的菌株(OspC基因类型)传递给正在进食的扁虱。也就是说，自然界中的每一种脊椎动物都充当着独特的生态位，感染并放大(传播给喂食者的)15种OspC基因的不同子集。因此，每种基因的丰度，包括那些对人类具有传染性的基因，都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哪些脊椎动物物种方面的因果作用尚未得到调查。这一建议的主要目的是确定感染包括人类在内的脊椎动物物种的能力在不同基因型间的差异是否与OspC序列的差异有关。我们将通过整合分子、生物和种群三个层面的生物复杂性来评估寄主选择性基因型的原因和公共卫生后果，以解决莱姆病生态和进化中的基本问题。通过人类疫苗控制目前的莱姆病疫情似乎还需要很多年的时间才能实现。减少人类感染OspC基因的丰度是减少莱姆病发病率的一种替代、有效和长期的解决方案。然而，为了达到这一目的，干预策略需要从分子到种群水平对伯氏杆菌的基本生物学有坚实的了解。这项建议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，这可能有助于生态控制策略的设计或疫苗开发。在短期内，这些研究将导致对脊椎动物物种传染性的机械理解；很少有人知道决定病原体物种可以感染的动物宿主范围的功能基础的例子。从全球疾病生态学的角度来看，这项工作是相关的，因为在种群内，宿主物种选择性保持的多态可能是许多新出现的传染病生态的一个显著特征。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壁虱传播疾病。然而，我们对导致人类侵袭性或增加人类莱姆病风险的机制知之甚少。这项建议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，这可能有助于生态控制策略的设计或疫苗开发。

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.