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

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.