Submitted to: Virus Research
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 2/2/2007
Publication Date: 6/1/2007
Citation: Bendfeldt, S., Ridpath, J.F., Neill, J.D. 2007. Activation of cell signaling pathways is dependant on the biotype of bovine viral diarrhea virus type 2. Virus Research. 126(1-2):96-105. Interpretive Summary: Bovine viral diarrhea virus (BVDV) is a ubiquitous virus of ruminants. There are currently 2 recognized forms of the virus, the noncytopathic and cytopathic biotypes. There is also a third proposed biotype, the lymphocytopathic biotype. The BVDV-infected cells respond differently to infection by the different biotypes. Infection of the susceptible animal by BVDV causes an array of different disease syndromes, each being BVDV strain dependent. It is believed that the severity of the disease is determined by both viral and host factors. It is unknown how this occurs or what determines the particular response. To examine how the cell responds to infection by BVDV, we looked at how the virus affects different cellular signaling pathways. The noncytopathic low virulence strain caused no changes in signaling pathways. Infection with the cytopathic strain was associated with activation of stress pathways and cell death within 24 hours. Infection with a highly virulent noncytopathic strain resulted in activation of survival pathways. This may explain earlier observations that highly virulent strains take up to 7 days to kill the infected cells. However, the manner in which the cell is killed is different from that of the cytopathic strains. These results are the first describing the effect of BVDV on intracellular signaling pathways and is the basis of future studies to further explore how these viruses alter the cell and affect the outcome of disease.
Technical Abstract: Bovine viral diarrhea virus (BVDV), a pestivirus of the Flaviviridae family, is an economically important cattle pathogen with a world wide distribution. Besides the segregation into two distinct species (BVDV1 / BVDV2) two different biotypes, a cytopathic (cp) and a noncytopathic (ncp) biotype, are distinguished based on their behavior in epithelial cell cultures. One of the most serious forms of BVDV infection affecting immunocompetent animals of all ages is severe acute BVD (sa BVD) which is caused by highly virulent BVDV2 strains. The severity of the disease does not correlate with the cytopathogenicity in vitro since the virulent viruses are all noncytopathogenic in cultured epithelial cells. Previous studies revealed that these highly virulent ncp viruses as well as cp viruses cause cell death in a lymphoid cell line (BL3) while low virulence strains do not, thus proposing the existence of a third biotype termed lymphocytopathic. To gain an insight into the molecular mechanisms of infection with highly virulent ncp BVDV2 we compared the effect of infection with different BVDV2 strains on cellular signaling pathways in BL3 cells. While increasing levels of phosphorylated p38 MAPK were detected only in cells infected with cp BVDV2, highly virulent ncp BVDV2 was found to influence the phosphoinositide 3-kinase (PI3K)-Akt survival pathway. Together with the finding that infection with highly virulent ncp BVDV2 results in cell death which is different from that of cp BVDV2 induced apoptosis, our results suggest that highly virulent ncp BVDV2 strains have evolved different mechanisms to modulate the antiviral response of the infected host cell.