Divergent transcriptomic trajectories in CD4/CD8ß/TcR1 bead-enriched peripheral lymphocyte fraction following experimental infection with low- and high-virulence strains of noncytopathic bovine viral diarrhea virus type 2

Authors: BAUERMANN, FERNANDO - Oklahoma State University; Bayles, Darrell; FALKENBERG, SHOLLIE - Auburn University; MAGGIOLI, MAYARA - Oklahoma State University; RIDPATH, JULIA - Retired ARS Employee

Submitted to: Virus Research
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 4/22/2026
Publication Date: 4/23/2026
Citation: Bauermann, F.V., Bayles, D.O., Falkenberg, S.M., Maggioli, M.F., Ridpath, J.F. 2026. Divergent transcriptomic trajectories in CD4/CD8ß/TcR1 bead-enriched peripheral lymphocyte fraction following experimental infection with low- and high-virulence strains of noncytopathic bovine viral diarrhea virus type 2. Virus Research. https://doi.org/10.1016/j.virusres.2026.199732.
DOI: https://doi.org/10.1016/j.virusres.2026.199732

Interpretive Summary: The Problem. Bovine viral diarrhea virus (BVDV) is a major disease affecting cattle production. Some strains of the virus cause mild illness, while others lead to severe disease with long-lasting immune damage, secondary infections, and increased risk of death. Farmers and veterinarians have long observed these differences, but it has remained unclear why some strains are so much more harmful. An identified knowledge gap was that there was little known about how different strains of BVDV affect T cells, the critical immune cells that fight infections and coordinate long-term immunity. The Accomplishment. This work determined how calves’ T cells respond to BVDV infection with either low-virulence or high-virulence strains of BVDV. Using advanced gene-sequencing technology, we measured which genes were turned on or off in T cells early after infection and again later during recovery. We found that calves infected with low-virulence strains mounted a strong but well-controlled immune response that gradually returned to normal. In contrast, high-virulence strains caused prolonged immune disruption: T cells showed signs of exhaustion, reduced ability to recognize new infectious agents, impaired communication with other immune cells, and continued inflammatory stress long after infection began. Contribution to Solving the Problem. These findings help explain why high-virulence BVDV causes more severe and lasting disease. Rather than simply overwhelming the immune system, highly virulent strains appear to derail it, damaging the very T cells needed for recovery. By identifying the specific immune pathways that fail during severe infection, this work provides new targets for improving vaccines and developing treatments that protect or restore immune function. Ultimately, this knowledge can support better disease control strategies, healthier cattle, and reduced economic losses for producers.

Technical Abstract: Bovine Viral Diarrhea Virus (BVDV) is a globally significant cattle pathogen that disrupts immune function and predisposes animals to secondary diseases. High-virulence BVDV strains are associated with severe lymphoid depletion and immune dysregulation, not observed in infections with low-virulence strains. The difference in specific transcriptional alterations in T-cells following infection with high and low virulence strains is undefined. In this study, we performed RNA-seq analysis of purified T-cells from calves experimentally infected with either high- or low-virulence BVDV strains, collected at 3 and 15 days post-infection (dpi), to identify virulence-specific transcriptome signatures. At 3 dpi, low-virulence BVDV elicited a coordinated antiviral response marked by strong induction of interferon-stimulated genes (ISG15, MX1, OAS family), inflammatory chemokines (CXCL8, CXCL10), and apoptotic mediators, consistent with effective viral sensing and clearance. In contrast, high-virulence BVDV induced a strong, but lower-magnitude interferon signature. A marked suppression of T-cell receptor signaling and cytotoxicity-associated genes (CD8A, LCK, CXCR4) was observed, suggesting functional impairment and altered trafficking. By 15 dpi, low-virulence infection transitioned toward immune resolution, with enrichment of metabolic recovery and proliferative pathways, whereas high-virulence infection maintained chronic inflammatory and proliferative signatures, broad suppression of antigen presentation (MHC class II), co-stimulatory signaling, and adaptive immune coordination. These results suggest that differences observed between infections with high and low virulence BVDV is associated with divergent T-cell transcriptomic trajectories, with high-virulence strains promoting prolonged immune activation and suppression of adaptive function. Targeting pathways that restore T-cell activation and metabolic resilience may enhance therapeutic and vaccine strategies against BVDV.