| dc.contributor.advisor | Pöhlmann, Stefan Prof. Dr. | |
| dc.contributor.author | Gonzalez Hernandez, Mariana | |
| dc.date.accessioned | 2019-03-28T09:20:22Z | |
| dc.date.available | 2019-03-28T09:20:22Z | |
| dc.date.issued | 2019-03-28 | |
| dc.identifier.uri | http://hdl.handle.net/11858/00-1735-0000-002E-E5EE-7 | |
| dc.identifier.uri | http://dx.doi.org/10.53846/goediss-7373 | |
| dc.language.iso | eng | de |
| dc.rights.uri | http://creativecommons.org/licenses/by-nc-nd/4.0/ | |
| dc.subject.ddc | 570 | de |
| dc.title | Interactions of the Ebola virus glycoprotein with host cell factors during viral entry and release | de |
| dc.type | doctoralThesis | de |
| dc.contributor.referee | Walter, Lutz Prof. Dr. | |
| dc.date.examination | 2019-03-18 | |
| dc.description.abstracteng | Ebola virus disease (EVD) is a severe disease that affects humans and non-human primates. The recent EVD epidemic in West Africa shows that EVD poses a severe threat to human health. EVD is caused by Ebola virus (EBOV) and other ebolaviruses, which belong to the family Filoviridae. The EBOV glycoprotein (GP) is the only viral surface protein and mediates host cell entry. Processing of GP by host cell proteases (priming) is required for viral entry into target cells and cathepsin (Cat) B and L have been implicated in GP priming in cell culture. However, these enzymes may be dispensable for viral spread in the infected host and the determinants governing CatB/L dependence of viral entry are incompletely understood. Therefore, the first goal of this thesis was to identify such determinants. Apart from mediating viral entry, EBOV-GP also promotes viral release by antagonizing the interferon-induced antiviral host cell protein tetherin. However, the domains in GP that govern counteraction of tetherin and the contribution of this process to viral spread are incompletely understood. The second aim of the present thesis was thus to identify GP domains and amino acid motifs that control tetherin antagonism.
The results of the present thesis show that EBOV-GP-driven entry depends on CatB/L activity irrespective of the shape of the viral particle and the target cell type. Moreover, Calu-3, a human cell line with low endogenous CatL expression, was found to be largely resistant to entry driven by EBOV-GP and other filovirus GPs. Finally, entry was restored by directed expression of CatL or the attachment promoting factor DC-SIGN. Regarding tetherin counteraction by GP, the results obtained show that a GXXXA motif in the transmembrane domain of GP is largely dispensable for GP expression, particle incorporation and host cell entry but is required for tetherin antagonism. Lack of tetherin antagonism was observed in transfected cells and was confirmed in the context of an infectious vesicular stomatitis virus chimera encoding EBOV-GP. In summary, the present thesis identifies Calu-3 cells as one of the few cell lines largely resistant to filovirus GP-driven entry and shows that entry is limited at the stage of attachment and GP priming. Moreover, the results identify a GXXXA motif in GP as essential for tetherin antagonism and provide the first evidence that antagonism can promote viral spread, at least in the context of a surrogate system. | de |
| dc.contributor.coReferee | Groß, Uwe Prof. Dr. | |
| dc.contributor.thirdReferee | Becker, Stephan Prof. Dr. | |
| dc.subject.eng | Ebola virus | de |
| dc.subject.eng | glycoprotein | de |
| dc.subject.eng | attachment factors | de |
| dc.subject.eng | cathepsins | de |
| dc.subject.eng | tetherin | de |
| dc.identifier.urn | urn:nbn:de:gbv:7-11858/00-1735-0000-002E-E5EE-7-7 | |
| dc.affiliation.institute | Göttinger Graduiertenschule für Neurowissenschaften, Biophysik und molekulare Biowissenschaften (GGNB) | de |
| dc.subject.gokfull | Biologie (PPN619462639) | de |
| dc.identifier.ppn | 1666649740 | |