Emerging flea-borne rickettsial diseases: vector competence and transmission biology

新出现的跳蚤传播立克次体疾病：媒介能力和传播生物学

• 批准号: 9179593
• 负责人: Kevin R. Macaluso
• 金额: $ 37万
• 依托单位: LOUISIANA STATE UNIV A&M COL BATON ROUGE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-12-01 至 2020-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9179593
• 关键词: Adult; Africa; Arthropod Vectors; Arthropods; Asia; Biological; Biology; Bite; Blood; California; Cessation of life; Characteristics; Communicable Diseases; Competence; Complex; Crowding; Data; Disease; Disease Management; Disease Outbreaks; Disease Vectors; Ecosystem; Endemic Flea-Borne Typhus; Environment; Epidemic Louse-Borne Typhus; Epidemiology; Europe; Event; Feces; Felis catus; Fleas; Genus Felis; Goals; Horizontal Disease Transmission; Hour; Human; Infection; Ingestion; Insecta; Intervention; Knowledge; Life Cycle Stages; Maintenance; Modeling; Molecular; Moscow; Mutagenesis; North America; Oceania; Pathogenicity; Population; Probability; Production; Publishing; Rattus; Recording of previous events; Reporting; Research; Resources; Retreatment; Rickettsia; Rickettsia Infections; Rickettsia felis; Rickettsia typhi; Rickettsiales; Route; Soldier; South America; System; Testing; Texas; Ticks; United States; Vertebrates; Vertical Disease Transmission; comparative; comparative genomics; design; experience; experimental study; feeding; innovation; killings; mutant; novel; novel strategies; pathogen; protein profiling; public health relevance; response; suburb; transcriptomics; transmission process; vector

 DESCRIPTION (provided by applicant): Rickettsia felis was originally identified in the United States as a human pathogen in 1991 and is now associated with human infection in North and South America, Europe, Africa, Asia, and Oceania. Our ultimate goal for this research is to elucidate the biological and molecular mechanisms that are critical to rickettsial transmission by fleas in order to better understand the epidemiology of flea-borne rickettsial diseases and identify novel points of intervention. The results of the proposed studies will determine if R. fels utilizes multiple mechanisms for rapid horizontal transmission between fleas independent of a rickettsemic vertebrate host. This is a new paradigm for vector-borne rickettsial diseases. Also, the probability that a novel rickettsial response occurs in the arthropod host, and is somehow associated with rickettsial transmission, has long been a tenant of vector-borne rickettsial diseases; however, this has never been tested in an actual transmission system. The experimental focus of this application is to delineate horizontal transmission mechanisms through comparative analyses three distinct rickettsial strains in two different arthropod vectors, cat fleas and rat fleas. The rickettsial-derived molecules underlying the transmission of R. felis in flea hosts are not known. Studies will also employ rickettsial mutagenesis to identify transmission determinants in a flea transmission system. Two limiting factors for vector/disease management and the barriers to advancing the field are the scant knowledge of 1) basic transmission biology of R. felis and, 2) the rickettsial-derived determinants of transmission. Through completion of the specific aims outlined in this application, these studies will overcome the hurdles by assessing rickettsial transmission by fleas (Specific Aim 1) and through identification of Rickettsia-derived molecular constituents essential to transmission events (Specific Aim 2). Thus, this is a multifaceted approach to decipher the vector and pathogen-associated factors essential to transmission and will provide a platform to examine other flea-borne bacterial pathogens. Aim 1. Delineate the mechanism by which Rickettsia felis is acquired and transmitted by arthropods. Stable vertical transmission of certain vector-borne pathogens eliminates the need for a vertebrate host; however, unless this transmission event is 100% efficient, additional horizontal amplification is required for maintenance of the pathogen in the environment. We will test the hypothesis that if vertical transmission of R. felis by fleas is not 100%, then horizontal transmission of R. felis must occur between fleas. The objective of this aim is to identify novel routes of R. felis acquisition by fleas and assess the intra- and inter-specific transmission of R. felis. Aim 2. Define the Rickettsia-derived molecular constituents of transmission by flea vectors. Vector-borne bacterial pathogens undergo essential molecular transformation in the vector prior to transmission to the vertebrate host. We will test the hypothesis that if R. felis expresses a distinct rickettsial protein profile that orchestrates infetion of arthropods and subsequent transmission, then disruption of key molecules will impede infection and/or transmission. To test this hypothesis, we will focus on (a) targeted mutagenesis in R. felis and (b) analysis of isogenic rickettsial mutants in flea-infection and transmission.

 描述（由适用提供）：Rickettsia Felis最初在1991年在美国被确定为人类病原体，现在与北美，欧洲，欧洲，非洲，亚洲和大洋洲的人类感染有关。这项研究的最终目标是阐明跳蚤对立克式传播至关重要的生物学和分子机制，以便更好地了解跳蚤式立克疾病的流行病学并确定新颖的干预点。拟议研究的结果将确定R.蝇是否利用多种机制来在跳蚤之间快速水平传播，而与立克脊椎动物宿主无关。这是矢量传播的立克疾病的新范式。同样，新颖的立克反应发生在节肢动物宿主中，并且以某种方式与立克的传播有关，长期以来一直是矢量传播的立克疾病的租户。但是，这从未在实际的传输系统中进行测试。该应用的实验重点是通过比较分析在两个不同的节肢动物载体中的三种不同的立克菌株来描述水平传输机制，即 猫跳蚤和大鼠跳蚤。尚不清楚跳蚤宿主在跳蚤宿主中传播的背后的立克衍生分子。研究还将采用立克​​诱变来识别跳蚤传播系统中的传播确定剂。媒介/疾病管理的两个限制因素以及前进该领域的障碍是1）R。Felis的基本传播生物学以及2）Rickettsial衍生的传播确定的范围。通过完成本应用中概述的特定目的，这些研究将通过评估跳蚤的立克传播（特定的目标1）以及鉴定立克衍生的分子构成传播事件必不可少的（特定目标2）来克服障碍。这是一种多方面的方法，可解读载体和与病原体相关的传播的相关因素，并将提供一个检查其他跳蚤细菌病原体的平台。 AIM 1。描述Rickettsia felis被节肢动物获取和传播的机制。某些载体传播病原体的稳定垂直传播消除了对脊椎动物宿主的需求；但是，除非该传输事件有100％效率，否则要维持环境中的病原体需要额外的水平扩增。我们将检验以下假设：如果跳蚤将felis垂直传播不是100％，那么R. felis的水平传播必须发生在跳蚤之间。此目的的目的是通过跳蚤鉴定出新的Felis R. felis的新途径，并评估R. felis的特异性和特异性传播。 AIM 2。定义跳蚤向量传播传播的立克衍生的分子构成。载体传播的细菌病原体在向脊椎动物宿主传播之前会在载体中进行基本的分子转化。我们将检验以下假设：如果R. felis表达了独特的立克蛋白谱，该蛋白质谱系策划了节肢动物的触发和随后的传播，那么关键分子的破坏将妨碍感染和/或传播。为了检验这一假设，我们将重点介绍（a）在felis的靶向诱变和（b）在跳蚤感染和传播中分析等源性立克突变体的分析。