Molecular determinants in cell entry of porcine pestiviruses

• Applicant: Privatdozent Dr. Alexander Postel
• Subject Area: Veterinary Medical Science
• Term: since 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 427829762

The genus Pestivirus belongs to the virus family Flaviviridae and comprises RNA viruses of great relevance, like Bovine viral diarrhea virus (BVDV) and Classical swine fever virus (CSFV), which are causative pathogens of notifiable diseases. Since decades, it was commonly accepted that pestivirus infections are restricted to cloven hooved (ungulate) hosts. In the past years, several atypical pestiviruses have been discovered in non-ungulate hosts. These newly discovered pestiviruses show the typical genome organization, but are genetically highly distinct. Obviously, these novel viruses represent a new group within the pestiviruses with so far uncharacterized biological properties. In addition, such a novel pestivirus was also discovered in pigs and designated „atypical porcine pestivirus“ (APPV). APPV causes a neurological disease in newborn piglets (congenital tremor) and involvement in other diseases (e.g. infertility, abortion, neonatal malformations) appears likely.Within this research project, it was possible to adapt APPV to cell culture conditions and to propagate it. The availability of a virus isolate provided the basis for further studies to characterize the biological properties of the pathogen. Our work demonstrated that there are obviously significant differences in the cell entry of APPV and CSFV. It has been believed for long time that the complement-regulating protein CD46 is the key for pestiviruses to penetrate the host cell, but our work showed that some pestiviruses - including CSFV - use a CD46-independent mechanism for cell entry. Which cellular surface structures are used instead for cell entry is still unclear and will be the subject of further research.The aim of the study is to provide insights into the complex, probably multi-step process of cell entry. Within this project is the aim to identify the molecular determinants of cell entry of pestiviruses and to characterize them in more detail. Several host cell factors have already been identified which apparently interact with the viral envelope proteins during early phases of viral replication and can influence virus replication. First, it has to be elucidated whether these factors directly interact with the virus particles or whether these are indirect effects, e.g. caused by binding to other cellular proteins or by an altered cell metabolism. Knowledge of the key factors for the entry of porcine pestiviruses into the host cell can make a valuable contribution to understanding the biology of the new and widespread pathogen in the pig population, APPV, as well as the properties of the long-known animal disease pathogen CSFV.

• DFG Programme: Research Grants