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Immune Factors Guiding Listeria Monocytogenes Infection

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Immune Factors Guiding Listeria Monocytogenes Infection FAKULTÄT FÜR MEDIZIN DER TECHNISCHEN UNIVERSITÄT MÜNCHEN Lehrstuhl für Medizinische Mikrobiologie, Immunologie und Hygiene Immune factors guiding Listeria monocytogenes infection Steven Phillip Broadley Vollständiger Abdruck der Fakultät für Medizin der Technischen Universität München zur Erlangung des akademischen Grades eines Doktors der Naturwissenschaften genehmigten Dissertation. Vorsitzender: Univ.-Prof. Dr. M. Göttlicher Prüfer der Dissertation: 1. Univ.-Prof. Dr. D. Busch 2. apl. Prof. Dr. Th. M. Fuchs Die Dissertation wurde am 15.09.2015 bei der Technischen Universität München eingereicht und durch die Fakultät für Medizin am 16.12.2015 angenommen. Summary I Summary Under normal conditions blood is sterile. Should bacteria reach the bloodstream, they must be removed rapidly to prevent the development of life-threatening diseases. Two organs dominate clearance of bacteria from the bloodstream: the liver, primarily known for destruction of pathogens, and the spleen, where antigen is used to prime long-lasting immune responses. Systemically circulating Listeria monocytogenes (L.m.) have been reported to bind murine blood platelets dependent on complement factor 3 (C3) and the platelet receptor Glycoprotein Ib (GPIb). Disruption of binding resulted in a faster clearance of L.m. from the bloodstream. The aim of this thesis was to investigate the process of L.m. – platelet complex formation and how binding to platelets alters the fate of systemically circulating L.m.. Light transmission platelet aggregometry revealed the process of L.m. – platelet interaction to consist of three distinct phases: I) Opsonization of L.m. with C3, II) formation of L.m. – platelet complexes dependent on C3 and GPIb, and III) activation and aggregation of platelets around complexed L.m. dependent on Immunoglobulin G. Utilizing 2-photon intravital imaging, novel positron-emission tomography and flow cytometry analysis it was found that clearance of systemically circulating L.m. is predominantly facilitated by hepatic Kupffer cells, who utilize two distinct mechanisms for the clearance of either non-platelet bound L.m. or L.m. – platelet complexes from the circulation: Uptake of non-platelet bound L.m. was found to depend on class A scavenger receptors (SRA), while uptake of L.m. – platelet complexes depended on the complement receptor of the immunoglobulin superfamily (CRIg). SRA-mediated clearance was found to be more efficient in the uptake and destruction of L.m. than its CRIg dependent counterpart. The slower clearance of L.m. – platelet complexes led to increased localization of L.m. to other organs, especially the spleen. CRIg-mediated clearance of bacteria-platelet complexes was also observed after systemic infection with other Gram (+) and Gram (-) bacteria, such as Enterococcus faecalis and Escherichia coli. A lack of clearance of L.m. – platelet complexes led to bacterial localization to the lung, indicating that aggregation of platelets around L.m., as had been observed in vitro, possibly led to the formation of microthrombi. Taken together, the data presented in this thesis indicate following process: After systemic infection Kupffer cells rapidly remove and destroy non-platelet bound L.m. from the circulation via SRA-mediated uptake. A portion of circulating L.m. binds to platelets, shifting hepatic clearance to CRIg-dependent uptake. CRIg-mediated clearance of L.m. from the bloodstream is slower than initial SRA-mediated clearance, thus allowing a small but important amount of bacterial localization to the spleen, where the antigen is used to prime adaptive immune responses. Zusammenfassung II Zusammenfassung Normalerweise ist Blut steril. Gelangen Bakterien in die Blutbahn, müssen sie schnellstmöglich entfernt werden um lebensgefährliche Krankheiten zu vermeiden. Bakterien werden hauptsächlich von zwei Organen aus der Blutbahn gefiltert: Der Leber, in der Bakterien zerstört werden, und der Milz, in der bakterielles Antigen zur Ausbildung einer lang anhaltenden Immunantwort genutzt wird. Es wurde gezeigt, dass in der Maus systemisch zirkulierende Listeria monocytogenes (L.m.) Blutplättchen mittels Komplementfaktor 3 (C3) und dem Plättchen-Rezeptor Glykoprotein Ib (GPIb) binden. Wurde diese Komplexbildung durch Plättchen, C3 oder GPIb Defizienz unterbunden, so wurden zirkulierende L.m. schneller aus der Blutbahn entfernt als im Wildtypen. Ziel dieser Dissertation war es, Vorgänge und Auswirkungen der Komplexbildung zwischen L.m. und Plättchen zu untersuchen. Licht-Transmissions-Aggregometrie zeigte, dass die Interaktion zwischen L.m. und Plättchen aus drei individuellen Phasen besteht: I) Der Opsonisierung von L.m. mit C3, II) Der Bildung von L.m.-Plättchen Komplexen abhängig von C3 und GPIb und III) Der Aktivierung und Aggregation von Plättchen um gebundene L.m. abhängig von Immunoglobulin G (IgG). Mittels intravitaler 2-Photonenmikroskopie, Positronen-Emissions-Tomographie und Durchfluss- zytometrie wurde herausgefunden, dass Kupffer-Zellen der Leber den Großteil zirkulierender L.m. aus dem Blut entfernen, wobei zwei verschiedene Mechanismen die Aufnahme von freien L.m. und L.m.-Plättchen-Komplexen bewerkstelligten: Während freie L.m. in Abhängigkeit von Klasse A Scavenger Rezeptoren (SRA) aufgenommen wurden, war die Aufnahme von L.m. – Plättchen-Komplexen abhängig von dem Komplementrezeptor der Immunoglobulin Superfamilie (CRIg). Die Entfernung freier L.m. aus der Blutbahn mittels SRA geschah schneller als die Entfernung komplexgebundener L.m. mittels CRIg und zerstörte L.m. effektiver. Durch die langsamere Komplexentfernung gelangen Bakterien zu anderen Organen, insbesondere zur Milz. CRIg-abhängige Aufnahme von Bakterien-Plättchen-Komplexen wurde ebenfalls nach systemischer Infektion mit anderen Gram (+) und Gram (-) Bakterien beobachtet, wie z.B. Ent. faecalis oder E. coli. Ohne CRIg-vermittelte Aufnahme von L.m.-Plättchen-Komplexen kam es zu einer Lokalisation von L.m. in der Lunge, was darauf hindeutet, dass Plättchenaktivierung und -aggregation um gebundene L.m. die Bildung von Mikrothrombi bedingen könnte. Zusammenfassend deuten die Ergebnisse dieser Dissertation auf folgenden Ablauf hin: Nach systemischer Infektion entfernen Kupffer-Zellen rasch freie L.m. mittels SRA. Ein Teil der L.m. bindet an Plättchen und wird mittels CRIg von den Kupffer-Zellen entfernt. L.m. Aufnahme durch CRIg ist langsamer als durch SRA und ermöglicht so einem kleinen Teil der L.m. das Erreichen der Milz, wo das bakterielle Antigen zur Generierung einer adaptiven Immunantwort verwendet wird. III Table of contents Summary ........................................................................................................................... I Zusammenfassung ............................................................................................................ II Table of contents ............................................................................................................. III List of figures, tables and illustrations .............................................................................. VI List of abbreviations ........................................................................................................ IX 1 Introduction ............................................................................................................... 1 1.1 Liver morphology ....................................................................................................... 1 1.2 The complement system ............................................................................................ 3 1.3 Phagocytic receptors .................................................................................................. 5 1.3.1 Complement receptors .......................................................................................... 5 1.3.2 Pattern recognition receptors ................................................................................ 7 1.4 Phagocytes ............................................................................................................... 10 1.4.1 Neutrophil Granulocytes ...................................................................................... 10 1.4.2 Kupffer cells .......................................................................................................... 11 1.5 Platelets .................................................................................................................... 13 1.6 Listeria monocytogenes ............................................................................................ 14 1.7 Aim of this thesis ...................................................................................................... 16 2 Results ..................................................................................................................... 18 2.1 Intravital microscopy of L.m. – platelet complexes in the bloodstream ................. 18 2.2 In vitro analysis of L.m. – platelet interactions ........................................................ 22 2.3 Bodily distribution of L.m. depends on complex formation .................................... 29 2.4 Hepatic uptake of L.m. is facilitated predominantly by Kupffer cells ...................... 34 2.5 Clearance of nonopsonized L.m. is facilitated by scavenger receptors ................... 43 2.6 Complement receptor CRIg influences clearance of L.m. from the bloodstream at later timepoints ...................................................................................................................
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