Gene expression links consistent immune and inflammatory pathways to bovine respiratory disease in high-risk stocker cattle

Abstract Bovine respiratory disease (BRD) remains the leading cause of morbidity and economic loss in North American cattle production. Cattle at high risk of BRD are often managed through antimicrobial metaphylaxis, although there are growing concerns regarding the use of antimicrobial drugs in food animals. To better understand host immunological responses to BRD and the effects of metaphylaxis, this study evaluated whole-blood gene expression patterns in high-risk stocker heifers using RNA sequencing (RNA-Seq). Eighty-four commercial heifers were randomly assigned to receive metaphylaxis with tulathromycin (META) or no metaphylaxis (NO META) upon arrival. Cattle were monitored over a 70-day period for clinical BRD, with whole blood collected from a subset of 60 heifers across multiple timepoints in both cattle that developed (TREAT) or failed to develop BRD (HEALTHY) for RNA-Seq. Principal component and differential gene expression analyses (FDR ≤ 0.05) were conducted to explore transcriptomic differences associated with BRD diagnosis over time, metaphylactic treatment, and disease severity. Minimal differences in the transcriptome were observed between META and NO META cattle at the time of BRD diagnosis, while comparisons between HEALTHY and TREAT cattle at onset of clinical disease revealed greater than 2000 differentially expressed genes (DEGs), with significant functional enrichment of immune-related pathways, including cytokine signaling, lymphocyte activation, and inflammatory responses. Notably, five genes (IL1R2, HP, S100A9, TLR4, and ALOX15) were consistently up- or downregulated in BRD cases, regardless of study group allocation. These observations align with previous studies, which support their candidacy as useful biomarkers for BRD detection. Despite the significant changes observed at the onset of clinical BRD, no differences were identified among these animals at the start of the study. This inability to predict future disease development or severity may have been affected by the low morbidity rate observed in this cohort. Expression of genes coding for heat shock proteins at subsequent treatments suggested that these may be useful markers of disease persistence or severity. These findings suggest that while metaphylaxis reduces BRD incidence, host transcriptomic profiles at disease onset offer improved insight into BRD pathophysiology.