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

• Applicant: Professor Dr. Ulf B. Göbel
• Co-Applicants: Professor Dr. Ziad A. Abdeen; Professor Amer Al-Jawabreh, Ph.D.; Professor Dr. Marc Victor Assous; Professor Dr. Herve Bercovier
• Subject Area: Immunology
• Term: from 2007 to 2010
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 28157173

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.

• DFG Programme: Research Grants
• International Connection: Israel, Palestine
• Participating Person: Professorin Dr. Annette Moter