Location: Animal Health GenomicsTitle: ADAM17 is an essential factor for the infection of bovine cells with pestiviruses
|ZARUBA, MARIANNE - University Of Veterinary Medicine|
|CHEN, HANN-WEI - University Of Veterinary Medicine|
|PIETSCH, OLE - University Of Veterinary Medicine|
|SZAKMARY-BRAENDLE, KATI - University Of Veterinary Medicine|
|AUER, ANGELIKA - University Of Veterinary Medicine|
|MOTZ, MARLENE - University Of Veterinary Medicine|
|SEITZ, KERSTIN - University Of Veterinary Medicine|
|DUESTERHOEFT, STEFAN - Aachen University|
|RUEMENAPF, TILL - University Of Veterinary Medicine|
|RIEDEL, CHRISTIANE - University Of Veterinary Medicine|
Submitted to: Viruses
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 2/7/2022
Publication Date: 2/13/2022
Citation: Zaruba, M., Chen, H., Pietsch, O.F., Szakmary-Braendle, K., Auer, A., Motz, M., Seitz, K., Dusterhoft, S., Workman, A.M., Rumenapf, T., Riedel, C. 2022. ADAM17 is an essential factor for the infection of bovine cells with pestiviruses. Viruses. 14(2). Article 381. https://doi.org/10.3390/v14020381.
Interpretive Summary: Bovine viral diarrhea virus (BVDV) is an important pathogen of cattle that causes significant morbidity and mortality. BVDV entry into susceptible host cells is a multi-step process and the complete set of host factors required for virus entry is unknown. ADAM17 was recently reported to be an essential cellular attachment factor for the closely related classical swine fever virus. To determine whether ADAM17 might be involved in BVDV entry, ADAM17 mRNA and protein expression was measured in two closely related cell lines: Madin-Darby bovine kidney cells (MDBK; fully susceptible to BVDV infection) and CRIB-1 cells (a derivative of MDBK cells resistant to BVDV infection at the level of virus entry). ADAM17 was detectable in MDBK cells but not CRIB-1 cells. Restoring ADAM17 expression in CRIB-1 cells rendered the once resistant cell line susceptible to BVDV infection. Thus, this study demonstrated that ADAM17 is a key cellular factor missing in CRIB-1 cells leading to BVDV resistance and establishes an essential role for ADAM17 in the entry of BVDV and related viruses into bovine cells. The identification of cellular factors involved in BVDV entry helps our understanding of cellular tropism and could facilitate the development of novel intervention strategies against BVDV.
Technical Abstract: The entry of BVDV into bovine cells was studied using CRIB cells (cells resistant to infection with bovine viral diarrhea virus [BVDV]) that have evolved from MDBK cells by a spontaneous loss of susceptibility to BVDV. Recently, larger genetic deletions were reported but no correlation of the affected genes and the resistance to BVDV infection could be established. The metalloprotease ADAM17 was reported as an essential attachment factor for the related classical swine fever virus (CSFV). To assess whether ADAM17 might be involved in the resistance of CRIB-1 cells to pestiviruses, we analyzed its expression in CRIB-1 and MDBK cells. While ADAM17 protein was detectable in MBDK cells, it was absent from CRIB-1 cells. No functional full-length ADAM17 mRNA could be detected in CRIB cells and genetic analysis revealed the presence of two defective alleles. Transcomplementation of functional ADAM17 derived from MDBK cells in CRIB-1 cells resulted in a nearly complete reversion of their resistance to pestiviral infection. Our results demonstrate that ADAM17 is a key cellular factor for the pestivirus resistance of CRIB-1 cells and establishes its essential role for a broader range of pestiviruses.