Bovine digital dermatitis (BDD) is a common infectious disease of digital skin in cattle and an important cause of lameness worldwide, with limited treatment options. It is of increasing global concern for both animal welfare and food security, imposing a large economic burden on cattle farming industries each year. A polytreponemal etiology has been consistently identified, with three key phylogroups implicated globally: Treponema medium, Treponema phagedenis, and Treponema pedis. Pathogenic mechanisms which might enable targeted treatment/therapeutic development are poorly defined. This study used RNA sequencing to determine global differential mRNA expression in primary bovine foot skin fibroblasts following challenge with three representative BDD treponemes and a commensal treponeme, Treponema ruminis. A pro-inflammatory response was elicited by the BDD treponemes, mediated through IL-8/IL-17 signaling. Unexpectedly, the three BDD treponemes elicited distinct mechanisms of pathogenesis. T. phagedenis and T. pedis increased abundance of mRNA transcripts associated with apoptosis, while T. medium and T. pedis increased transcripts involved in actin rearrangement and loss of cell adhesion, likely promoting tissue invasion. The upregulation of antimicrobial peptide precursor, DEFB123, by T. phagedenis spirochaetes may present a microbial ecological advantage to all treponemes within BDD infected tissue, explaining their dominance within lesions. A commensal, T. ruminis, significantly dysregulated over three times the number of host mRNA transcripts compared to BDD treponemes, implying BDD treponemes, akin to the syphilis pathogen (Treponema pallidum), have evolved as “stealth pathogens” which avoid triggering substantial host immune/inflammatory responses to enable persistence and tissue invasion. Immunohistochemistry demonstrated increased IL-6, IL-8, RND1, and CFB protein expression in BDD lesions, confirming in vitro fibroblast observations and highlighting the system’s value in modeling BDD pathogenesis. Several unique shared gene targets were identified, particularly RGS16, GRO1, MAFF, and ZC3H12A. The three key BDD Treponema phylogroups elicited both distinct and shared pathogenic mechanisms in bovine foot skin; upregulating inflammation whilst simultaneously suppressing adaptive immunity. The novel gene targets identified here should enable future vaccine/therapeutic approaches.

牛数字皮肤炎（BDD）是牛中数字皮肤的常见传染病，并且是全世界la行的重要原因，治疗选择有限。全球对动物福利和粮食安全的关注日益增加，每年给养牛业带来巨大的经济负担。一词多态性的病因已得到一致鉴定，全球涉及三个关键的系统群：密螺旋体培养基和 足螺旋体可能使靶向治疗/治疗发展成为可能的致病机制还不清楚。这项研究使用RNA测序来确定原始牛足部皮肤成纤维细胞在受到三种代表性BDD座标和共鸣座标攻击后的总体差异mRNA表达，鲁米螺旋体。BDD色氨酸引起促炎反应，介导通过IL-8 / IL-17信号。出乎意料的是，这三个BDD座席引起了独特的发病机理。豆 和 足癣 与凋亡相关的mRNA转录物增加，而 T.中等 和 足癣增加的转录本参与肌动蛋白重排和细胞粘附丧失，可能促进组织浸润。抗菌肽前体DEFB123的上调豆螺线虫可能会对BDD感染组织内的所有色氨酸提供微生物生态优势，从而说明它们在病变中的优势。赞美的鲁米尼，其宿主mRNA转录物的数量显着失调，是BDD色氨酸的三倍，这意味着BDD色氨酸类似于梅毒病原体（梅毒螺旋体）已演变为“隐身病原体”，可避免触发大量的宿主免疫/炎症反应以实现持久性和组织侵袭。免疫组化显示BDD病变中IL-6，IL-8，RND1和CFB蛋白表达增加，证实体外成纤维细胞的观察，并突出了该系统在BDD发病机理建模中的价值。确定了几个独特的共有基因靶标，特别是RGS16， GRO1， 马夫和 ZC3H12A。BDD的三个关键梅毒螺旋体系统群在牛足部皮肤中引起不同的和共同的致病机制。上调炎症，同时抑制适应性免疫。此处确定的新型基因靶标应能支持未来的疫苗/治疗方法。