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Dissemination of Borrelia Burgdorferi, the Agent of Lyme Borreliosis, in Comparison to Borrelia Persica, the Agent of Tick-Borne Relapsing Fever, in a Murine Model

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Dissemination of Borrelia Burgdorferi, the Agent of Lyme Borreliosis, in Comparison to Borrelia Persica, the Agent of Tick-Borne Relapsing Fever, in a Murine Model Dissemination of Borrelia burgdorferi, the Agent of Lyme Borreliosis, in Comparison to Borrelia persica, the Agent of Tick-Borne Relapsing Fever, in a Murine Model von Liucun Liang Inaugural-Dissertation zur Erlangung der Doktorwürde der Tierärztlichen Fakultät der Ludwig-Maximilians-Universität München Dissemination of Borrelia burgdorferi, the Agent of Lyme Borreliosis, in Comparison to Borrelia persica, the Agent of Tick-Borne Relapsing Fever, in a Murine Model von Liucun Liang aus Henan, VR China München 2019 Aus dem Veterinärwissenschaftlichen Department der Tierärztlichen Fakultät der Ludwig-Maximilians-Universität München Lehrstuhl für Bakteriologie und Mykologie Arbeit angefertigt unter der Leitung von: Univ.-Prof. Dr. Reinhard K. Straubinger, Ph.D. Gedruckt mit der Genehmigung der Tierärztlichen Fakultät der Ludwig-Maximilians-Universität München Dekan: Univ.-Prof. Dr. Reinhard K. Straubinger, Ph.D. Berichterstatter: Univ.-Prof. Dr. Reinhard K. Straubinger, Ph.D. Korreferent: Univ.-Prof. Dr. Rüdiger Wanke Tag der Promotion: 27. Juli 2019 For my family For Stefan Gruhler and his family Content V Content I INTRODUCTION................................................................................................. 1 II LITERATURE REVIEW ..................................................................................... 3 1 Historical background .......................................................................................... 3 1.1 Tick-borne relapsing fever (TBRF) ........................................................................ 3 1.2 Lyme borreliosis (LB) ............................................................................................. 3 2 Etiology and epidemiology .................................................................................... 4 2.1 Taxonomy and nomenclature of Borrelia spirochetes ............................................ 4 2.2 Pathogenic TBRF and LB Borrelia species ............................................................ 6 2.2.1 TBRF Borrelia species throughout the world ......................................................... 6 2.2.2 LB Borrelia genospecies in the Northern Hemisphere ........................................... 7 2.2.3 Cell morphology and outer membrane proteins.................................................... 10 2.3 The enzootic cycle of TBRF and LB Borrelia ...................................................... 12 2.3.1 Transmission vectors ............................................................................................. 12 2.3.2 Life cycle of TBRF and LB organisms ................................................................. 16 2.3.3 Reservoirs and hosts ............................................................................................. 17 3 Pathogenesis of TBRF and LB organisms in mammalian host ....................... 19 3.1 Tick-assisted immune evasion .............................................................................. 19 3.2 Adaptation of borreliae during transmission......................................................... 19 3.3 Establishment of early infection ........................................................................... 21 3.4 Susceptibility to host complement system ............................................................ 25 3.5 Immune evasion by borrelial antigenic variations ................................................ 26 3.5.1 Variable major proteins of TBRF Borrelia ........................................................... 26 3.5.2 Variable major protein-like sequence of LB Borrelia ........................................... 28 3.6 Persistence of Borrelia infection in mammalian host tissues ............................... 28 3.6.1 Residual brain infection of TBRF spirochetes ...................................................... 28 3.6.2 Invasion of LB spirochetes in host tissues ............................................................ 29 3.7 Patterns of Borrelia dissemination in mammalian host ........................................ 30 3.7.1 Hematogenous dissemination of TBRF borrelia ................................................... 30 3.7.2 Controversial dissemination pathways of LB borrelia .......................................... 31 III STUDY HYPOTHESIS AND OBJECTIVE .................................................... 35 IV ANIMALS, MATERIALS AND METHODS ................................................... 36 1 Experimental design ............................................................................................ 36 Content VI 2 Animals ................................................................................................................. 36 2.1 Immunodeficient NOD-SCID mouse ................................................................... 37 2.2 Immunocompetent C3H/HeOuJ mouse ................................................................ 37 2.3 Mouse hygiene and handling management ........................................................... 37 3 Borrelial strains and cultivation ........................................................................ 40 3.1 Bp LMU-01 and Bbss N40 .................................................................................... 40 3.2 Preparation of spirochetes for initial inoculation using in vitro culture ............... 40 4 Experimental procedures .................................................................................... 42 4.1 Negative control group ......................................................................................... 42 4.2 Generation of host-adapted borreliae in NOD-SCID mice ................................... 43 4.2.1 Intradermal inoculation of culture-derived spirochetes ........................................ 43 4.2.2 Dynamic detection of host-adapted borreliae in blood ......................................... 44 4.2.3 Harvesting of host-adapted borreliae in blood ...................................................... 45 4.2.4 Collection of tissue samples for cultivation and PCR testing ............................... 46 4.3 Inoculation of host-adapted borreliae into C3H/HeOuJ mice ............................... 46 4.3.1 Intradermal inoculation of host-adapted borreliae ................................................ 46 4.3.2 Strict intravenous inoculation of host-adapted borreliae ...................................... 47 4.3.3 Blood collection, plasma and serum samples ....................................................... 50 4.3.4 Culture of spirochetes from blood and tissue samples.......................................... 51 4.4 Detection and quantification of borrelial DNA in blood and tissue samples ........ 52 4.4.1 DNA extraction ..................................................................................................... 52 4.4.2 PCR testing ........................................................................................................... 53 4.5 Serological analysis .............................................................................................. 55 4.5.1 ELISA ................................................................................................................... 55 4.5.2 LIA ........................................................................................................................ 56 4.6 Statistics and data analysis .................................................................................... 58 V RESULTS ............................................................................................................. 59 1 Population kinetics of host-adapted borreliae in the blood of immunodeficient NOD-SCID mice .................................................................... 59 1.1 Kinetics of host-adapted Bp spirochetes ............................................................... 59 1.2 Kinetics of host-adapted Bbss spirochetes ............................................................ 61 2 Distribution of borreliae in tissues of NOD-SCID mice ................................... 63 3 Population kinetics of borreliae in the blood of immunocompetent C3H/HeOuJ mice ................................................................................................. 65 Content VII 3.1 Population kinetics of Bp spirochetes in blood ..................................................... 65 3.2 Population kinetics of Bbss spirochetes in blood .................................................. 66 4 Distribution of borreliae in tissues of C3H/HeOuJ mice ................................. 67 4.1 Bp in tissues .......................................................................................................... 67 4.2 Bbss in tissues ....................................................................................................... 68 5 Specific antibodies against Bp and Bbss in C3H/HeOuJ mice ........................ 70 5.1 Kinetics of specific antibody response against Bp ................................................ 70 5.2 Kinetics of specific antibody response against Bbss............................................. 71 5.3 Visualization of specific antibodies against Bbss ................................................. 73 VI DISCUSSION ...................................................................................................... 74 1 Host-adapted Bp and Bbss organisms ............................................................... 75 2 Intravenous inoculation via jugular vein but not tail vein .............................. 76 3 Spirochetemia and
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