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: 8131135
• 负责人: Dustin Brisson
• 金额: $ 34.7万
• 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 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8131135
• 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; Epidemic; Evolution; Genetic; Genetic Polymorphism; Genotype; Goals; Health; Human; Incidence; Insecta; Intervention; Laboratories; Lead; Lyme Disease; Modeling; Molecular; Nature; Order Spirochaetales; Organism; OspC protein; Patients; Peptide Hydrolases; Plasminogen; Play; Population; Predisposition; Process; Public Health; 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）：从动物传播到人类的疾病是威胁人类健康的新兴传染病。莱姆病是由Borlelia burgdorferi细菌引起的，它影响于美国其他任何其他节肢动物传播（由昆虫或tick虫携带）的人更多的人。但是，人类不能被所有B. burgdorferi菌株感染。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种OSPC变体中，在莱姆病患者中分离出的菌株中只有5种。同样，每种野性脊椎动物物种都将基因型不同菌株（OSPC基因型）的独特子集传播到喂食壁虱。也就是说，自然界中的每种脊椎动物物种都充当了感染并放大的独特生态基因（传输到喂食ticks），这是15个OSPC基因型的不同子集。因此，每个基因型的丰度，包括感染人类的​​基因型，由脊椎动物物种的组成和相对密度决定。但是，OSPC在确定菌株可能感染的脊椎动物物种中的因果作用尚未研究。该提案的主要目的是确定基因型中感染脊椎动物物种（包括人类）的能力的变化是否与OSPC序列的差异有因果关系。我们将通过整合三个层次的生物复杂性来评估基因型宿主选择性的原因和公共卫生后果；分子，生物和种群 - 解决莱姆病生态和进化中的基本问题。通过人类疫苗控制当前的莱姆病流行似乎已经有很多年了。减少人类感染性的OSPC基因型是减少莱姆病发病率的替代，有效且长期的解决方案。然而，对此的干预策略需要从分子到人口水平的B. burgdorferi的基本生物学有深入的了解。该提案的长期目标是确定分子和生态学的机械原因，这些原因有助于人类莱姆病风险，这可能有助于设计生态控制策略或疫苗开发。在短期内，这些研究将导致对脊椎动物物种感染性的机械理解。很少有人知道，确定动物宿主可以感染动物的范围的功能基础。从全球疾病生态学的角度来看，这项工作与宿主物种选择性维持的人群多态性有关，这可能是许多新兴传染病的生态学的重要特征。在短期内，这些研究将为影响动物传播病原体的自然丰富性和疾病风险的因素提供基本的新见解。莱姆病是美国最普遍的昆虫或tick虫传播疾病。然而，我们对有助于人类侵入性或升级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分子和生态学的机械原因，这些原因有助于人类莱姆病风险，这可能有助于设计生态控制策略或疫苗开发。

项目成果

Explosive radiation of a bacterial species group.

• DOI: 10.1111/j.1558-5646.2012.01598.x
• 发表时间: 2012-08
• 期刊: Evolution; international journal of organic evolution
• 作者: Morlon H;Kemps BD;Plotkin JB;Brisson D
• 通讯作者: Brisson D

The effect of spatial heterogenity on the aggregation of ticks on white-footed mice.

• DOI: 10.1017/s003118201200008x
• 发表时间: 2012-06
• 期刊: Parasitology
• 影响因子: 2.4
• 作者: Devevey G;Brisson D
• 通讯作者: Brisson D

Detecting Lyme disease using antibody-functionalized single-walled carbon nanotube transistors.

• DOI: 10.1016/j.bios.2013.01.035
• 发表时间: 2013-07-15
• 期刊: BIOSENSORS & BIOELECTRONICS
• 影响因子: 12.6
• 作者: Lerner, Mitchell B.;Dailey, Jennifer;Goldsmith, Brett R.;Brisson, Dustin;Johnson, A. T. Charlie
• 通讯作者: Johnson, A. T. Charlie

Reductions in human Lyme disease risk due to the effects of oral vaccination on tick-to-mouse and mouse-to-tick transmission.

由于口服疫苗对蜱到小鼠和小鼠到蜱传播的影响，降低了人类莱姆病的风险。

• DOI: 10.1089/vbz.2012.1003
• 发表时间: 2013
• 期刊: Vector borne and zoonotic diseases (Larchmont, N.Y.)
• 作者: Voordouw,MaartenJ;Tupper,Haley;Önder,Özlem;Devevey,Godefroy;Graves,ChristopherJ;Kemps,BrianD;Brisson,Dustin
• 通讯作者: Brisson,Dustin

Identifying sources of tick blood meals using unidentified tandem mass spectral libraries.

• DOI: 10.1038/ncomms2730
• 发表时间: 2013
• 期刊: Nature communications
• 影响因子: 16.6