Dokument

Zusammenfassung:
Aus Vögeln stammende Influenza-A-Viren (IAV) können im Menschen einen schweren Krankheitsverlauf verursachen. Unter den diversen Subtypen, die vom Vogel auf den Menschen übertragen werden, sind vor allem die Subtypen H5N1 und H7N9 von besonderem Interesse, da sie für IAV-Ausbrüche mit hohen Mortalitätsraten verantwortlich sind. Diese Viren werden gelegentlich vom Vogel auf den Menschen übertragen und stellen deswegen ein pandemisches Risiko dar. Während der Infektion müssen IAV verschiedene wirtsspezifische Verteidigungsmechanismen der angeborenen Immunantwort überwinden, deren Effekt auf die Infektion durch IAV nicht vollständig bekannt ist. In dieser Arbeit sollte die Interaktion von IAV mit zwei Faktoren der angeborenen Immunantwort näher untersucht werden: die Interaktion von IAV mit humanem Atemwegsmucus und die Interaktion mit IFN-induzierten antiviralen Proteinen. Im Menschen replizieren IAV im Epithel des Respirationstraktes. Das Epithel ist dabei von einer Mucusschicht bedeckt. Mucine, welche hochgradig glykosilierte sialinsäurehaltige Proteine sind, bilden dabei den Hauptanteil des Mucus aus. Sie dienen als extrazelluläre Rezeptoren für Pathogene, wie zum Beispiel Viren. Im Allgemeinen wird angenommen, dass humane Mucine hauptsächlich α2-3-verknüpfte Sialinsäuren exprimieren und dass aviäre Viren sensitiver gegenüber der Neutralisation durch Mucus sind als humane Viren (Couceiro et al., 1993). Neuere Studien hingegen zeigen, dass humane Viren sensitiver gegenüber Mucus sind als aviäre Viren. Im ersten Teil der Arbeit sollte diese Diskrepanz in der Literatur und der inhibitorische Effekt von Mucus aus humanen tracheo-bronchialen Epithel (HTBE)-Kulturen auf die IAV-Infektion untersucht werden. Es konnte gezeigt werden, dass die Inhibition abhängig vom genutzten Zellsystem war. Im Standardzellsystem, MDCK-Zellen, zeigte das humane saisonale Virus eine hohe Sensitivität gegenüber Mucus, während die Infektion aviärer Viren nicht inhibiert wurde. Dahingegen zeigten das aviäre und das humane Virus in HTBE-Kulturen eine vergleichbare Inhibition durch Mucus. Dieses Ergebnis wurde dadurch unterstützt, dass aviäre und humane Viren Mucus im vergleichbaren Ausmaß banden. Um die inhibitorischen Komponenten im Mucus zu identifizieren, wurden die Mucuseigenschaften bestimmt. Dabei konnte festgestellt werden, dass die Mucusproben sowohl α2-6- als auch α2-3-verknüpfte Sialinsäuren aufweisen und dass die Inhibition von IAV abhängig von den Sialinsäuren im Mucus ist. Zusammenfassend lässt sich sagen, dass sowohl aviäre als auch humane Viren durch humanen bronchialen Mucus inhibiert werden. Dies widerspricht der allgemeinen Hypothese, dass aviäre Viren sensitiver gegenüber bronchialen Mucus sind als humane Viren. Im zweiten Teil dieser Arbeit wurde untersucht, inwiefern die Eigenschaften des HAs und der NA die Virussensitivität gegenüber dem IFN-β-induzierten antiviralen Status beeinflussen. Dafür wurden rekombinante Viren hergestellt, die das HA und NA repräsentativer aviärer, zoonotischer und humaner Viren sowie die internen Gene des Laborstammes A/Puerto Rico/8/1934 besitzen. IFN-β wird während der initialen Phase einer Virusinfektion sezerniert und induziert die Expression mehrerer hundert sogenannter Interferon-stimulierter Gene (ISGs). Diese Proteine können eine antivirale Aktivität aufweisen wie zum Beispiel die Interferon-induzierte-Transmembran-Protein-Familie (IFITM), welche die Fusion zwischen viralen und zellulären Membranen inhibieren. Der genaue Wirkmechanismus der IFITM-Proteine ist jedoch nicht bekannt. Die Virussensitivität gegenüber dem antiviralen Status korrelierte mit dem pH-Optimum der Fusion. Viren mit einem hohen pH-Optimum der Fusion, wie zum Beispiel Viren, die das HA und NA der zoonotischen Viren H5N1 und H7N9 besaßen, infizierten mit IFN-β vorstimulierte Zellen effizienter als die Viren mit einem niedrigen pH-Optimum der Fusion. Dieses Ergebnis wurde bestätigt, indem rekombinante Viren getestet wurden, die einzelne Punktmutationen im HA des A/Hong Kong/1/1968 besaßen, die das pH-Optimum der Fusion beeinflussten. In Übereinstimmung mit den Ergebnissen der rekombinanten Viren wiesen die korrespondierenden Wildtypisolate des H5N1-, des H7N9-Virus und des pandemischen Virus von 2009 ein höheres pH-Optimum der Fusion sowie eine geringere Sensitivität gegenüber dem IFN-β-induzierten antiviralen Status auf als das pandemische Virus von 1968 und ein humanes saisonales Virus. Es wurde bereits beschrieben, dass IFITM-Proteine wirksame Inhibitoren der viralen Fusion sind. In dieser Arbeit wird gezeigt, dass die Inhibition von Viren durch IFITM-Proteine abhängig vom pH-Optimum der viralen Fusion ist. Viren mit einem hohem Fusions-pH, wie zum Beispiel H5N1 und H7N9, zeigten eine geringere Reduktion der Infektion in MDCK-Zellen, welche das humane IFITM2 und IFITM3 stabil exprimierten, als Viren mit einem niedrigen Fusions-pH. Die Ergebnisse dieser Arbeit zeigen zum ersten Mal, dass das pH-Optimum der Fusion die Virussensitivität gegenüber IFN-induzierten Effektormolekülen, inklusive IFITM-Proteine, beeinflusst. Diese Daten deuten des Weiteren darauf hin, dass das hohe pH-Optimum der Fusion zoonotischer Viren, wie zum Beispiel das H5N1- und das H7N9-Virus, zu ihrer Fähigkeit beitragen könnte, den Menschen zu infizieren und schwere Krankheitsverläufe zu verursachen.

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