Structure and function analyses of the Hantavirus envelope glycoproteins and their role in virus assembly, virus entry and immune recognition, as novel targets for antiviral treatment


Hantaviruses (HV), which belong to the Bunyaviridae family of RNA viruses, are emerging pathogens that cause life threatening human zoonoses with case fatalities reaching 50% and is ranked among the top five reportable virus infections by the Robert Koch Institute in Berlin. In spite of their medical importance, our knowledge of HV biology is extremely fragmentary. This project focuses on HV envelope glycoproteins Gn and Gc, which form a heterodimer exposed at the virus surface, carrying the main viral antigenic determinants. Both are responsible for entry into host cells by recognizing a receptor at the plasma membrane and by catalyzing membrane fusion in the endosomes after receptor-mediated endocytosis. The heterodimer also plays a crucial role in the morphogenesis of newly formed HV via interaction of the cytosolic domains with the viral genomic RNA and by driving virion assembly and budding. This project will be tackled by a consortium of four complementary groups, combining experts in molecular virology, cell and structural biology, biochemistry and biophysics to provide an in-depth analysis of the glycoproteins and their crucial interactions with other cellular and viral factors including the segmented HV RNA genome. Crystallization in complex with receptor or neutralizing antibodies will allow the identification of vulnerable sites for antiviral intervention. Assembly and interaction of Gn/Gc will be characterized using approaches ranging from super resolution microscopy to mass spectrometry. Host molecules interacting with the glycoproteins will be identified by two independent methods and validated for biological relevance by RNAi. Synthetic peptides will be used to assign and to affect the glycoproteins functional domains. Our results will characterize potential interactions to be targeted for therapeutic intervention, e.g. the receptor-binding site, the fusogenic conformational change and the cytosolic domain that binds the genomic RNA for budding.


Principal Investigators
Herrmann, Andreas Prof. Dr. rer. nat. (Details) (Molecular Biophysics)

Duration of Project
Start date: 04/2016
End date: 12/2019

Publications
Sperber, H.S., Welke, R.-W., Petazzi, R.A., Bergmann, R., Schade, M., Shai, Y., Chiantia, S., Herrmann, A.*, Schwarzer, R.* (2019) Self-association and subcellular localization of Puumala hantavirus envelope proteins. Sci. Rep., 2019 Jan 24;9(1):707. doi: 10.1038/s41598-018-36879-y (*corr. authors)

Last updated on 2020-12-11 at 16:45