Human Cytomegalovirus Cell Entry in Primary Fibroblasts
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1 Diss. ETH N o Human Cytomegalovirus Cell Entry in Primary Fibroblasts Adissertationsubmittedto ETH ZURICH for the degree of Doctor of Sciences presented by STEFANIE ELFRIEDE GERDA HETZENECKER Diplom in Biology, University of Regensburg born January 22 nd,1984 citizen of Germany accepted on the recommendation of Prof. Ari Helenius, examiner Prof. Urs Greber, co-examiner 2014
2 Summary Human Cytomegalovirus (HCMV) is the prototype member of the -herpesvirus family. HCMV infection is wide-spread in the human population and an important contribution to disease in immunocompromised patient groups. Despite decades of research dedicated to the biology of herpesviruses, there is currently no vaccine available, and treatment options are limited. HCMV has broad tissue tropism and infects a variety of cell types. Infection in fibroblasts occurs in a clathrin- and ph-independent manner. It was therefore concluded that infectious entry in this cell type occurs by fusion at the plasma membrane. Little else is known about the entry process and cellular factors essential for infection in fibroblasts. Therefore, the aim of this thesis was to identify cellular factors required for early steps of the infection process and to elucidate the cell entry mechanism. For this, we developed assays to study early stages of the HCMV (AD169) infection process. The established assays allow quantitative measurement of virus infection (i.e. immediate early gene expression), virus binding, internalization, and tegument uncoating by western blotting, flow cytometry, and indirect immunofluorescence. The described assays were utilized to elucidate the cellular entry mechanism of HCMV. Electron microscopy revealed that virions reside in large vacuoles devoid of visible coats. This was confirmed by the observed colocalization of virions with EEA1- and Rab5-positive vacuoles in indirect immunofluorescence. Together, the findings indicated that HCMV undergoes endocytosis for host cell entry. The endocytic uptake mechanism was then characterized using a panel 1
3 2 of inhibitors targeting cellular factors involved in endocytosis. Virus infection was reduced by compounds inhibiting actin rearrangements, Na + /H + exchangers, dynamin II, and signaling pathways activated during macropinocytosis. The observed inhibitor profile strongly suggested that macropinocytosis mediates HCMV internalization into fibroblasts. Importantly, inhibition of Na + /H + exchangers decreased virus uptake. In further support of a macropinocytic uptake pathway, HCMV virions were found to reside in fluid-filled vesicles post entry. Macropinocytosis on the formation of actin-rich membrane protrusions that drive the internalization of extracellular fluids and particles in large vesicles called macropinosomes. By live imaging after HCMV addition, we observed the formation of circular dorsal ru es (CDRs) and large plasma membrane derived vacuoles. CDR formation is known to be dependent on dynamin II. Virus infection, internalization, and tegument uncoating were decreased upon dynamin inhibition, indicating that the dynamin dependent formation of CDRs is linked to virus uptake. Taken together our data demonstrated that in primary fibroblasts the productive entry pathway for HCMV virions involves macropinocytosis. Further, we report that HCMV is the first virus known to induce actin-rearrangements leading to CDR formation during its entry process.
4 Zusammenfassung Human Cytomegalovirus (HCMV) ist ein repräsensitiver Modellvirus der - Herpesvirus Familie. HMCV Infektionen sind in der menschlichen Bevölkerung weit verbreitet und tragen massgebend zu Erkrankungen in immunsupprimierten Patienten bei. Obwohl der Herpesvirus Biologie ein jahrzehntelanger Forschungseinsatz gewidmet wurde, gibt es bis heute keinen Impfsto zur Verhinderung von HCMV Infektionen und nur limitierte Behandlungsmöglichkeiten. HCMV zeichnet sich durch einen breiten Gewebetropismus aus und infiziert eine Vielzahl an Zelltypen. Die Infektion von Fibroblasten Zellen bedarf weder Clathrin-vermittelter Endozytose noch niedrigem ph. Aufgrund dieser Beobachtung wurde geschlossen, dass der infektöse Zelleintritt in Fibroblasten durch Fusion an der Zellmembran eingeleitet wird. Abgesehen davon ist wenig bekannt über den HCMV Zelleintrittsprozess und die zellulären Faktoren, welche für die Infektion von Fibroblasten essentiell sind. Deshalb war es die Zielsetzung dieser Doktorarbeit, die zellulären Faktoren, welche für frühe Stadien des Infektionsprozesses notwendig sind, zu identifizieren und weiterhin den Zelleintrittsmechanismus aufzuklären. In diesem Sinne entwickelten wir Protokolle, welche dazu dienen frühe Stadien des HCMV (AD169) Infektionsprozesses zu untersuchen. Die entwickelten Protokolle ermöglichen quantitative Messungen der HCMV Infektion ( immediate early Gen Exprimierung), der Virus-Internalisierung und des Verlusts von viralem Tegument ( Uncoating ) mithilfe von Western Blots, Durchflusszytometrie und indirekter Immunfluoreszenz. Anschliessend wurden diese Protokolle eingesetzt um den HCMV Zelleintrittsmechanismus o en 3
5 4 zu legen. Mithilfe von Elektronenmikroskopie konnten wir zeigen, dass HCMV Viren in grossen, unbemanntelten Vesikeln lokalisiert sind. Dies wurde bestärkt durch indirekte Immunfluoreszenz, welche die Kolokalisation von HCMV mit EEA1- and Rab5-positiven Vesikeln o enlegte. Zusammengefasst zeigen diese Beobachtungen, dass HCMV über Endozcytose in den Zellwirt gelangt. Der HCMV Zelleintrittsmechanismus wurde anschliessend mithilfe von Inhibitoren charakterisiert, welche gegen für Endozytose massgebende, zelluläre Faktoren gerichtet sind. Dabei war die HCMV Infektion reduziert in Gegenwart von Inhibitoren, welche die Umgestaltung von Aktinfilamenten, den Na + /H + Austausch, Dynamin II oder für Makropinozytose wichtige Signalwege unterbinden. Zusammen sind diese Faktoren ein wichtiges Indiz dafür, dass die HCMV Internalisierung in Fibroblasten über Makropinozytose erfolgt. Hervorzuheben ist zudem, dass die Inhibition von Na + /H + Austausch die Virus Internalisierung reduzierte. Ein weiterer Hinweis auf einen makropinozytotischen Zelleintrittsmechanismus war die Beobachtung, dass HCMV in mit extrazellulärer Flüssigkeit gefüllten Vesikeln lokalisiert. Die makropinozytotische Aufnahme von extrazellulärem Material wird über Aktin-reiche Membranvorstülpungen gesteuert. Diese vermitteln die Internalisierung von Flüssigkeiten und Partikeln in grosse Vesikel, Makropinosomen genannt. Mithilfe von mikroskopischen Aufnahmen lebender Zellen nach HCMV Zugabe konnten wir die Bildung von Circular Dorsal Ru els (CDRs) sowie von grossen, sich an der Zellmembran formenden, Vesikleln beobachten. Die Entstehung von CDRs benötigt zwingend Dynamin II. Interessanterweise waren Virus Infektion, Internalisierung und Tegument uncoating infolge von Dynamin Inhibition stark reduziert. Dies deutet darauf hin, dass die Dynamin abhängige CDR Bildung bei der Internalisierung von HCMV Viren eine wichtige Rolle spielt. Zusammengefasst zeigten unsere Resultate, dass der infektiöse Zelleintritt von HCMV in primären Fibroblasten über Makropinozytose erfolgt. Desweiteren konnten wir zeigen, dass HCMV in diesem Zelltyp weitgehende Veränderungen im Aktin Zytoskelett der Zelle hervorruft, welche zur Bildung
6 5 von CDRs führen. Erwähnenswerterweise ist dies die erste Studie, welche einen viralen Stimulus zur CDR Bildung beschreibt.
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