Publikationsserver der Universitätsbibliothek Marburg
Titel:Die Rolle des aviären PB1 Gens bei der Entstehung pandemischer Influenza-A-Viren
Autor:Wendel, Isabel
Weitere Beteiligte: Bremer, Erhard (Prof. Dr.)
Veröffentlicht:2014
URI:https://archiv.ub.uni-marburg.de/diss/z2014/0465
URN: urn:nbn:de:hebis:04-z2014-04656
DOI: https://doi.org/10.17192/z2014.0465
DDC: Biowissenschaften, Biologie
Titel (trans.):The Role of the avian PB1 gene in the emergence of pandemic Influenza viruses
Publikationsdatum:2015-05-28
Lizenz:https://rightsstatements.org/vocab/InC-NC/1.0/

Dokument

Schlagwörter:
viral transmission, virale Transmission, replication efficiency, Pandemie, Grippe, PB1 gene, PB1 Gen, Replikationseffizienz

Zusammenfassung:
Die pandemischen Influenza-Viren von 1957 und 1968 sind durch Reassortierung entstanden und tragen neben einem Hämagglutinin ebenfalls ein PB1-Gensegment aviären Ursprungs. Für das Hämagglutinin ist seit langem bekannt, dass Änderungen in dessen Epitopen entstehenden pandemischen Influenza-Viren ermöglichen der humanen Immunantwort zu entgehen. Im Gegensatz dazu ist die biologische Signifikanz des aviären PB1 bei der Entstehung pandemischer Influenza-Viren bislang noch ungeklärt. Ziel dieser Arbeit war es, diese seit langem bestehende Fragestellung zu untersuchen und aufzuklären, ob das aviäre PB1-Gen pandemischen Influenza-Viren einen replikativen Vorteil in humanen Zellen unterbreitet. Im ersten Teil dieser Arbeit wurde die Reassortierung, welche zur Entstehung des pandemischen Virus von 1968 führte, mit Hilfe der Gensegmente aviärer und humaner Vorläuferviren modelliert. Ausgehend von dem humanen H2N2 Vorläufervirus A/California/1/66 (Cal66) wurden zwei rekombinante Cal66-Viruspaare generiert, deren Viren sich lediglich im Ursprung des PB1-Gensegments unterscheiden (PB1Cal oder PB1HK) und die entweder das humane HA des Cal66-Virus oder das aviäre HA des pandemischen A/Hong Kong/1/68 (HK68) Virus enthalten. Um zu untersuchen, ob das aviäre PB1 die virale Replikations- und Transmissionseffizienz des pandemischen HK68-Virus steigerte, wurden kompetitive Infektionen in humanen Bronchial-Epithelzellen (Calu-3), sowie kompetitive Kontaktübertragungsstudien in Meerschweinchen durchgeführt. Für die kompetitiven Infektionen wurden zum einen 1:1 Mischungen von Viren mit aviärem (PB1HK) und humanem PB1 (PB1Cal) über drei Passagen in Calu-3-Zellen passagiert und die Zusammensetzung der nach Passage 3 erhaltenen Virusmischungen mittels Sanger-Sequenzierung bestimmt. Zum anderen wurden Viren, welche sich im PB1-Gensegment unterscheiden, mittels reverser Genetik kompetitiv generiert. Hierfür wurden Zellen mit einem kompletten Set reverser Genetik-Plasmide, sowie einer 1:1 Mischung der Plasmide PB1Cal und PB1HK transfiziert und die Zusammensetzung der erhaltenen Virusmischung mittels Sequenzierung bestimmt. Um die Kontaktübertragungseffizienz von Viren mit aviärem PB1 zu untersuchen, wurde eine Gruppe von vier Meerschweinchen mit einer 1:1 Mischung der Viren rCal-HAHK und rCal- (HA+PB1)HK infiziert. Einen Tag nach Inokulation wurden die inokulierten Tiere mit vier naiven Kontakttieren in Kontakt gebracht und an verschiedenen Tagen nach Inokulation wurden Nasenspülungen durchgeführt, die gesammelt und mittels Sequenzierung charakterisiert wurden. Im Rahmen der kompetitiven Replikationsstudien zeigte sich, dass Viren mit aviärem PB1, unabhängig vom Ursprung des HA-Gensegments, effizienter replizieren. Zudem wiesen humane Polymerasekomplexe mit aviärem PB1 eine erhöhte Polymerase-Aktivität auf, welche die beobachtete erhöhte virale Replikationseffizienz bedingen könnte. Im zweiten Teil dieser Arbeit wurde der Einfluss des aviären PB1 auf die virale Polymerase- Genauigkeit untersucht. Für das human-adaptierte aviäre PB1 des pandemischen HK68 Virus wurde beobachtet, dass dieses sich in drei human-adaptiven Mutationen von der aviären Konsensus-Sequenz unterscheidet. Um zu untersuchen, ob diese adaptiven Mutationen die Polymerase-Genauigkeit des entstehenden pandemischen Virus beeinflusst haben, wurden rekombinante HK68-Viren hergestellt, welche ein PB1 enthielten, das entweder an allen drei oder an einzelnen Aminosäure-Positionen die aviäre Konsensus-Sequenz aufwies. Für die Dreifach-Mutante mit aviär-ähnlichem PB1 war zu beobachten, dass diese gegenüber dem pandemischen HK68-Virus eine geringfügig erhöhte Mutations-Frequenz aufwies, während die Einzelmutanten rHK-PB1HK-V212L und rHK-PB1HK-K327R eine deutlich erhöhte Mutations- Frequenz zeigten. Diese Daten lassen vermuten, dass zunächst eine bzw. mehrere adaptive Mutationen die Polymerase-Genauigkeit der initialen Reassortante herabsetzten, während nach Adaptation der Reassortante an den Menschen durch Erwerb einer bzw. weiterer Mutationen die Polymerase-Genauigkeit wiederhergestellt wurde. Dieses Szenario würde mit der weithin akzeptierten Hypothese übereinstimmen, nach der zeitweilig reduzierte Polymerase-Genauigkeiten zu einer breiten Quasispezies-Diversität führen und somit zoonotischen Viren eine effiziente Adaptation an die neue Wirtsspezies ermöglichen. Zusammenfassend konnte im Rahmen dieser Arbeit gezeigt werden, dass das aviäre PB1-Gen des pandemischen HK68-Virus sowohl die virale Replikationseffizienz, als auch die virale Übertragungseffizienz, vermutlich in Folge einer erhöhten Polymerase-Aktivität steigerte. Zudem könnte eine zeitweilig reduzierte Polymerase-Genauigkeit die Adaptation der initialen Reassortante an den Menschen erleichtert und damit zur Entstehung der Pandemie von 1968 beigetragen haben.

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  39. Abb. IV.13: Reassortierungs-Szenarien die zur Entstehung des pandemischen HK68-Virus geführt haben könnten……………………………………………………………………………………….. 118
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  42. Abb. IV.2: Phylogenetischer Stammbaum der konkatenierten Gensegmente PB2-PA-NP-NA-M-NS humaner H2N2 Viren, isoliert in den Jahren 1965 bis 1968 und den pandemischen HK68-Viren…………………………………………………………………….. 92
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