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

疏螺旋体属由一群非同寻常的螺旋体组成，它们轻松地在食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引起，硬壳病是一种独特的疾病，在非洲、中亚、印度、地中海地区、美洲和中东都有流行。TBRF的致病螺旋体是由鸟形纲动物属的软体壁虱传播的。TBRF的特点是反复发烧，通常强度和持续时间减少，并伴有非特异性症状(如肌肉痛、头痛、胃肠道症状)。如果不进行抗生素治疗，它可能是致命的。由于大量螺旋体在外周血液中循环，不被免疫系统清除，因此能够入侵器官和神经系统，因此TBRF-疏螺旋体在螺旋体中具有特殊的地位，关于传播、入侵策略和致病机制仍有许多悬而未决的问题：-TBRF-疏螺旋体是否利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，入侵组织和中枢神经系统？-TBRF-疏螺旋体如何获得必需的营养，如氨基酸、核苷酸、酶辅助因子，以及来自宿主的脂肪酸？-宿主对螺旋体攻击的反应是什么？-TBRF-疏螺旋体如何与先天性免疫系统(IIS)相互作用？多年来，TBRF-疏螺旋体的Zaxonomy。是基于共物种形成的概念，这意味着某个疏螺旋体物种通常与一个不同的鸟形目物种相关联。疏螺旋体的准确鉴定。直到最近，当分子工具可用于螺旋体的检测和系统发育分化时，参与TBRF的人一直受到培养这些挑剔的微生物的困难的阻碍。虽然在中东是地方性的，但关于鸟形虫的数量和身份几乎没有任何信息。和疏螺旋体。在这一地区引发了急性呼吸窘迫综合征。然而，对所涉及的扁虱和疏螺旋体种类的明确识别对于解释实验结果、与临床参数的相关性和预防TBRF至关重要。因此，我们需要区分TBRF-疏螺旋体的种类，并研究它们在中东的流行情况、地理分布和动物储存库。小鼠模型的建立将有助于研究螺旋体的入侵，螺旋体与宿主的原位亲密相互作用，和对TBRF的先天免疫反应。在这项建议中，我们打算-鉴定和分类中东地区的TBRF的媒介和感染体-开发用于鉴定鸟形虫的分子工具-开发用于检测和鉴定TBRF的分子工具-疏螺旋体。-评估TBRF在中东的流行情况-评估中东的TBRF-疏螺旋体的动物储藏库-研究疏螺旋体与媒介的相互作用和趋化运动，根据螺旋体在硬壳体内的分布和间隔之间的转移-监测宿主中的螺旋体入侵途径-确定朝向宿主的先天免疫反应研究疏螺旋体-宿主-细胞相互作用与螺旋体入侵的关系，炎症反应和免疫反应-开发预防TBRF的方法-建立TBRF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为全面了解TBRF提供了独特的机会，突出了中东的流行病学方面和预防战略，也为疏螺旋体感染的发病和免疫提供了新的见解。这些实验将有助于理解TBRF的早期发病机制，这是潜在成功干预的前提。此外，小鼠模型与原位分析相结合，利用宿主细胞对细菌的微型表达分析，不仅可以回答TBRF的基本问题，而且可以解决许多感染生物学研究领域的基本问题。这种合作的结果将使农业土地得到更好的利用，更好的健康，更安全的旅游，基础微生物学和临床微生物学的长期合作，并将通过建立TBRF网络来加强学术基础设施和科学人力。

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.