|SCHAUT, ROBERT - Iowa State University|
Submitted to: PLoS ONE
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 7/7/2016
Publication Date: 7/15/2016
Publication URL: http://handle.nal.usda.gov/10113/62919
Citation: Schaut, R.G., Ridpath, J.F., Sacco, R.E. 2016. Bovine viral diarrhea virus type 2 impairs macrophage responsiveness to toll-like receptor ligation with the exception of toll-like receptor 7. PLoS One. 11(7):e0159491. doi: 10.1371/journal.pone.0159491.
Interpretive Summary: Bovine viral diarrhea virus (BVDV) infects cattle worldwide resulting in disease in both dairy and beef production units. In the present study, researchers from the National Animal Disease Center studied immune responses following infection of white blood cells with BVDV that were then stimulated with various compounds that mimic aspects of viral or bacterial infection. This was done as viral or bacterial infections can be seen in calves following BVDV infection. The results show that BVDV causes block of certain immune proteins in the cells in response to the bacterial and viral mimics, except for one viral mimic. These data provide novel information on the impact of infection with this cattle virus. Scientists trying to investigate methods to combat this virus would be beneficiaries of this current research, with the ultimate goal of providing intervention strategies to cattle producers.
Technical Abstract: Bovine viral diarrhea virus (BVDV) is a member of the Flaviviradae family. BVDV isolates are classified into two biotypes based on the development of cytopathic (cp) or non-cytopathic (ncp) effects in epithelial cell culture. In addition, BVDV isolates are further separated into species, BVDV1 and 2, based on genetic differences. Symptoms of BVDV infection range from subclinical to severe, depending on strain virulence, and may involve multiple organ systems and induction of a generalized immunosuppression. During BVDV-induced immune suppression, macrophages, critical to innate immunity, may have altered pathogen recognition receptor (PRR) signaling, including signaling through toll-like receptors (TLRs). Comparison of BVDV 2 strains with different biotypes and virulence levels is valuable to determining if there is a correlation between viral phenotypes and impaired macrophage responses. The current study demonstrates that cytopathic (cp), noncytopathic (ncp), high (hv) or low virulence (lv) BVDV2 infection of bovine monocyte-derived macrophages (MDMF) result in differential expression of pro-inflammatory cytokines compared to uninfected MDMF. A hallmark of cp BVDV2 infection is IL-6 production. As might be observed during secondary bacterial infection, cytokine secretion was markedly decreased in BVDV2-infected MDMF in response to TLR2 or 4 ligation, compared to non-infected MDMF. Macrophages were hyporesponsive to viral TLR3 or TLR8 ligation. However, TLR7 stimulation of BVDV2-infected MDMF induced c-Jun N-terminal kinase (JNK)1/2 phosphorylation. In addition, a unique isoform of p46 was observed. Together, these data suggest that BVDV2 infection suppressed proinflammatory cytokine protein responses to bacterial sensing TLRs in MDMF. However infected MDMF are not impaired in response to TLR7 stimulation. Overall, BVDV strains of varying virulence and biotype differentially induce proinflammatory cytokine mRNA, but each strain dampens cytokine responses to subsequent TLR ligation, with the exception of TLR7. These data provide novel information regarding potential pathways to target in combating BVDV and related secondary infections.