Bovine viral diarrhea virus 2 infection induces antiviral and remodeling transcriptional programs in the calf thymus.

Bovine viral diarrhea virus (BVDV) has marked tropism for lymphoid tissues and is associated with thymic atrophy and immune dysfunction in calves. However, the transcriptional programs associated with thymic injury and longer-term recovery remain incompletely defined. To characterize these responses, thymus transcriptomes were profiled by RNA sequencing following experimental BVDV-2 infection, with sampling during the post-acute phase at 13 days post-inoculation (pi) and at a later time (day 42 pi). This transcriptomic analysis was performed in the same calf cohort previously shown to develop variable long-term thymic atrophy and impaired IDV-specific cell-mediated responses after prior BVDV exposure. Post-acute BVDV exposure was associated with a strong thymic immune and antiviral transcriptional signature, with 295 differentially expressed transcripts relative to controls, including prominent chemokine, complement, and antigen-presentation-associated signals. At day 42 pi, relatively few transcripts differed in the broad comparison group, indicating attenuation of the early transcriptional response. In contrast, marked heterogeneity was evident among BVDV-exposed calves, with persistent thymic atrophy versus apparent recovery. Persistent thymic atrophy was associated with enrichment of cell-cycle, chromosome-organization, DNA metabolic, and extracellular-matrix-related programs. Targeted RT-qPCR analysis supported selected extracellular-matrix, spindle/cell-cycle, and lymphoid-development-associated expression differences between calves with persistent thymic atrophy and calves with apparent recovery. The day-42 thymic outcome analysis was exploratory because it involved a small subgroup of calves with persistent atrophy versus apparent recovery. Together, these findings provide a molecular context for the previously observed association between persistent thymic atrophy and weaker T-cell responses to subsequent IDV challenge.