Die pathogenetische Bedeutung des Endotheltropismus aviärer Influenzaviren

• Applicant: Professor Dr. Hans-Dieter Klenk (†)
• Subject Area: Virology
• Term: from 2002 to 2010
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 5389385

Fowl plague virus (FPV) has a high specificity for endothelial cells in the chick embryo. We could show that endotheliotropism is determined, on the one hand, by the high cleavability of the FPV he-magglutinin (HA) which mediates virus entry into the vascular system and, on the other hand, by polar virus budding from the apical side of endothelial cells and by restricted receptor expression which both prevent spread of infection into tissues surrounding endothelia. Since there is increasing evidence that the balance of virus binding mediated by HA and release mediated by the neuraminidase (NA) is an important determinant for the pathogenicity of avian influenza viruses, we would like to analyze in the first part of this project the impact of the interplay of HA and NA on endotheliotropism. For this purpose we will generate recombinant FPV viruses in which neuraminidase activity and receptor affinity are controlled by varying the length of the NA stalk and the number of oligosaccharides adjacent to the receptor binding pocket of HA, respectively. In the second part of the project we would like to analyze the role of FPV-induced apoptosis in endothelial permeability. To accomplish this we will generate FPV mutants that are unable to express either the pro-apoptotic PB1-F2 protein or the anti-apoptotic NS1 protein. These viruses will provide us with a system that allows up- and down-regulation of apoptosis and will thus enable us to analyze the effects of apoptosis on endothelia under controlled conditions.

• DFG Programme: Priority Programmes
• Subproject of: SPP 1130: Infections of the Endothelium