Upregulation of the type I interferon pathway in feedlot cattle persistently infected with bovine viral diarrhea virus

Authors: NILSON, SARA - University Of Nebraska; Workman, Aspen; SJEKLOCHA, DAVID - Cattle Empire, Llc; BRODERSEN, BRUCE - University Of Nebraska; GROTELUESCHEN, DALE - University Of Nebraska; PETERSEN, JESSICA - University Of Nebraska

Submitted to: Virus Research
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 1/8/2020
Publication Date: 3/1/2020
Citation: Nilson, S.M., Workman, A.M., Sjeklocha, D., Brodersen, B., Grotelueschen, D.M., Petersen, J.L. 2020. Upregulation of the type I interferon pathway in feedlot cattle persistently infected with bovine viral diarrhea virus. Virus Research. 278:197862. https://doi.org/10.1016/j.virusres.2020.197862.
DOI: https://doi.org/10.1016/j.virusres.2020.197862

Interpretive Summary: Bovine viral diarrhea virus (BVDV) is an economically important pathogen of cattle that can lead to a variety of clinical outcomes ranging from inapparent infection to severe disease involving multiple organ systems. When pregnant cows are infected, the virus can cross the placenta and infect the developing fetus. A persistent (lifelong) infection can be established in the fetus if the infection occurs before the maturation of the fetal immune system. Calves born persistently infected often have increased morbidity and mortality and serve as a continual source of viral exposure to herd mates. To gain a better understanding of how BVDV interacts with the host immune system to maintain a lifelong persistent infection, we looked at the RNA expression profiles in blood from mature, persistently infected (PI) feedlot cattle, cattle co-mingling with PI cattle but not themselves infected with the virus, and a group of unrelated, unexposed controls. Comparing RNA expression profiles between these groups of cattle revealed that cattle persistently infected with BVDV have significant upregulation of innate immune genes but not genes involved in an adaptive immune response when compared to uninfected controls. Furthermore, the RNA expression profile was not different between cattle infected with different genotypes of the virus, suggesting a common innate immune response to persistent infection with BVDV. This work represents the first study using mature cattle experiencing a natural, persistent infection with the virus combined with a whole-genome approach such as RNA-sequencing. This information builds upon our understanding of the molecular mechanisms through which the virus is able to establish and maintain persistent infection.

Technical Abstract: Bovine viral diarrhea virus (BVDV) has a profound economic impact on the cattle industry. Calves infected in utero and born persistently infected (PI) with BVDV have increased morbidity, mortality, and reduced productivity. Further, they serve as a continual source of viral exposure to herd mates and thereby pose a significant risk to animal wellbeing and production efficiency. Understanding the mechanisms through which PI is established and maintained is therefore important in working toward finding means to prevent or mitigate losses due to infection. Early studies of acute infection suggested BVDV infection alters the host’s ability to mount a type I interferon (IFN) response, thereby allowing for the establishment of PI. More recently, however, animals experimentally challenged with the virus demonstrated a chronic yet modest upregulation of the IFN pathway. To identify if the IFN or other pathways are altered due to PI by BVDV in a natural infection, the circulating blood transcriptome was analyzed from PI feedlot cattle (N = 10 BVDV1a, 8 BVDV1b, 8 BVDV2), cattle co-mingling with PI cattle but not themselves infected (N=9), and a group of unrelated, unexposed controls (N=10). Differential expression analyses included contrasts among BVDV subtypes, and all pair-wise comparisons of PI, co-mingled non-PI, and unexposed animals. Analyses in limma-voom revealed no difference in the transcriptome based upon the BVDV genotype with which the animal was infected. However, gene expression did differ (adj P < 0.05 and |logFC|>1) at 175 loci between the PI and co-housed, non-PI contemporaries and when compared to the unexposed controls, 489 loci were differentially expressed. Pathway analyses predict that alterations in the transcriptome of the PI cattle indicate significant upregulation of innate immune function including IFN signaling. These data support prior work suggesting IFN signaling is not completely suppressed in cattle naturally PI with BVDV.