Papillomatous digital dermatitis (PDD) is a polymicrobial infection in soft tissue adjacent to the hoof and is the leading cause of lameness in dairy cattle. Treponema phagedenis-like (TPL) spirochetes are a constant feature of PDD lesions and are localized deep in infected tissue. Host-cell response mechanisms to TPL spirochetes are poorly understood. To assess how bovine macrophages respond to cellular constituents of TPL spirochetes, changes in transcription were analyzed using serial analysis of gene expression (SAGE) and real time RT-PCR. This analysis revealed that some proinflammatory cytokines (e.g. GCP-2 and IL-8) are induced in treated macrophages, while receptors and their accessory proteins for IL-1, IL-6 and IL-11 are either down regulated or unchanged. Two genes encoding proteins having negative effects on NFkappaB, IkappaB and SIVA-1, are significantly induced in stimulated cells. Several genes associated with the cytoskeleton and antigen presentation are down regulated after exposure to sonicated TPL spirochetes, as are genes associated with wound repair. Combined, these data suggest that the innate immune and wound repair functions of bovine macrophages exposed to TPL cellular constituents are impaired thereby enabling bacteria to resist clearance and induce lesion formation. Use of this in vitro bovine macrophage model should be useful in elucidating host-spirochete interactions and facilitate identification of potential virulence traits.