TBRF in the Middle East: Prevalence, molecular characterization and pathogenesis

疏螺旋体属由一组特殊的螺旋体组成，它们可以轻松地在嗜血节肢动物和脊椎动物宿主之间穿梭。它在基因组组织、传播、入侵以及与宿主免疫系统的相互作用方面表现出独特的特征。虽然由多种疏螺旋体属引起，蜱传回归热（TBRF）是一种独特的疾病，在整个非洲、中亚、印度、地中海地区、美洲以及中东流行。TBRF的致病螺旋体是通过鸟蜱属的软蜱传播的。TBRF的特征是反复发作的发热，通常强度和持续时间降低，并伴有非特异性症状（例如肌痛、头痛、胃肠道症状）。如果没有抗生素治疗，它可能是致命的。由于外周血中循环的螺旋体数量非常高，不能被免疫系统清除，因此能够侵入器官和神经系统，TBRF-疏螺旋体物种在螺旋体中处于特殊的位置，有许多关于传播，入侵策略和发病机制的问题尚未解决：-TBRF-疏螺旋体是否使用趋化性在载体和宿主之间穿梭？- TBRF-疏螺旋体如何克服宿主的障碍并侵入组织和中枢神经 系统？TBRF-疏螺旋体如何从宿主获得必需的营养，如氨基酸，核苷酸，酶辅因子和脂肪酸？宿主对螺旋体攻击的反应是什么？TBRF-疏螺旋体如何与先天免疫系统（IIS）相互作用？多年来，TBRF-疏螺旋体属的Zaxonomy。是基于共同物种形成的概念，这意味着某种疏螺旋体物种通常与一种独特的Ornithodoros sp.有关。疏螺旋体属的准确鉴定。由于培养这些难养微生物的困难，直到最近，当分子工具可用于检测和螺旋体的遗传分化时，对TBRF的研究才受到阻碍。虽然在中东是地方性的，但几乎没有任何关于鸟类的数量和身份的信息。和疏螺旋体属（Borrelia spp.）导致该地区出现结核分枝杆菌RF。然而，明确识别蜱和疏螺旋体物种是必不可少的实验结果的解释，与临床参数和预防TBRF的相关性。因此，我们需要区分TBRF-疏螺旋体属物种，并研究它们在中东的流行率和地理分布以及动物感染。小鼠模型的建立将允许研究螺旋体入侵、Borrelia -宿主原位密切相互作用以及对TBRF的先天免疫应答。通过该提议，我们打算-鉴定和分类中东地区TBRF的载体和感染因子-开发用于鉴定Ornithodoros spp的分子工具。开发用于检测和鉴定TBRF-疏螺旋体属的分子工具-评估中东地区TBRF的患病率-评估中东地区TBRF-疏螺旋体的动物病原体-研究疏螺旋体-载体相互作用和在蜱虫内螺旋体分布方面的趋化运动以及蜱虫室之间的转移-监测宿主中螺旋体入侵途径-确定对TBRF-疏螺旋体属的先天免疫应答-研究疏螺旋体-宿主细胞在螺旋体入侵、炎症和免疫反应方面的相互作用-制定预防结核分枝杆菌RF的方法-建立结核分枝杆菌RF元数据库，用于合并和处理所有获得的数据。以色列、巴勒斯坦、约旦和德国合作伙伴之间的密切合作提供了独特的机会，可以全面了解结核分枝杆菌RF，突出中东的流行病学方面和预防战略，而且还为疏螺旋体感染的发病机制和免疫提供了新的见解。这些实验将有助于了解TBRF的早期发病机制，这是潜在成功干预的先决条件。小鼠模型结合原位分析，利用宿主细胞对细菌的反应的微型化表达分析，不仅可以回答TBRF的基本问题，而且可以回答感染生物学研究的许多领域的基本问题。通过建立一个TBRF网络，我们将在土地、更好的健康、更安全的旅游、基础微生物学和临床微生物学方面的长期合作等方面开展合作，并将加强学术基础设施和科学人才。

The genus Borrelia comprises an extraordinary group of spirochetes that shuttles between hematophagous arthropods and vertebrate hosts with ease. It exhibits unique features regarding genome organization, transmission, invasion, and interaction with the host’s immune system. Although caused by a variety of Borrelia spp., tick-born relapsing fever (TBRF) is a distinct disease that is endemic throughout Africa, central Asia, India, Mediterranean areas, America and also the Middle East. The causative spirochetes of TBRF are transmitted by soft ticks of the genus Ornithodoros. TBRF is characterized by recurring attacks of fever, usually of decreasing intensity and duration and accompanied by nonspecific symptoms (e.g. myalgia, headache, gastrointestinal symptoms). Without antibiotic treatment it may be fatal. With outstanding high numbers of spirochetes circulating in the peripheral blood, not being cleared by the immune system and therefore being able to invade organs and the nervous system, TBRF-Borrelia species assign to an exceptional position within the spirochetes with many still unsolved questions concerning transmission, invasion strategies and pathogenesis:- Do TBRF-Borreliae use chemotaxis to shuttle between vector and host?- How does TBRF-Borrelia overcome the host’s obstacles and invade tissues and the central nervous system?- How does TBRF-Borrelia gain access to essential nutrition like amino acids,nucleotides, enzyme cofactors, and fatty acids from the host?- What is the host’s response to the spirochete attack?- How does TBRF-Borrelia interact with the innate immune system (IIS)?For many years, the Zaxonomy of TBRF-Borrelia spp. was based on the concept of co-speciation, meaning that a certain Borrelia species is usually linked to a distinct Ornithodoros sp.. The exact identification of the Borrelia spp. involved in TBRF was hampered by difficulties in culturing these fastidious microorganisms until more recently, when molecular tools were available for detection and phylogenetical differentiation of the spirochetes. Although endemic in the Middle East, there is hardly any information about the number and identity of Ornithodoros spp. and Borrelia spp. causing TBRF in this region. However, unambiguous identification of the ticks and Borrelia species involved is essential for the interpretation of experimental results, correlation with clinical parameters and prevention of TBRF. We therefore need to differentiate the TBRF-Borrelia species and to study their prevalence and geographical distribution and animal reservoire in the Middle East. The establishment of a mouse model will allow the study of spirochete invasion, the intimate Borrelia – host interaction in situ, and the innate immune response to TBRF.With this proposal we intend to- Identify and classify the vectors and infectious agents of TBRF in the Middle East- Develop molecular tools for the identification of Ornithodoros spp.- Develop molecular tools for the detection and identification of the TBRF-Borrelia spp.- Assess the prevalence of TBRF in the Middle East- Assess the animal reservoire of TBRF-Borreliae in the Middle East- Study the Borrelia – vector interactions and chemotactic movements in terms of spirochete distribution within ticks and shift between the tick’s compartments- Monitor the spirochete invasion pathways in the host- Determine the innate immune response towards TBRF-Borrelia spp.- Study the Borrelia – host-cell interactions regarding spirochete invasion, inflammatory- and immunoreactions- Develop means of prevention of TBRF- Establish a TBRF-metadatabase for merging and processing of all obtained data.The close cooperation between the Israeli, Palestinian, Jordanian and German partners offers the unique opportunity to gain a comprehensive view on TBRF highlighting epidemiological aspects and prevention strategies in the Middle East, but also providing new insights in the pathogenesis and immunity of Borrelia infections. The experiments will contribute to the understanding of the early pathogenesis of TBRF, which is a prerequisite to a potential successful intervention.Furthermore, the mouse model in combination with in situ analysis using miniaturized expression analysis of host cells in response to bacteria could answer basic problems not only for TBRF but in many areas of infection biology research.The results from this collaboration will allow a better use of agricultural land, better health, safer tourism, long term cooperation in basic microbiology and clinical microbiology and will result in strengthening the academic infrastructure and scientific manpower by building up a TBRF-network.