Department of Infection Biology, Institute of Infection and Global Health, University of Liverpool, Liverpool, United Kingdom.
Front Cell Infect Microbiol. 2021 Jan 8;10:538591. doi: 10.3389/fcimb.2020.538591. eCollection 2020.
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: , and 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, . A pro-inflammatory response was elicited by the BDD treponemes, mediated through signaling. Unexpectedly, the three BDD treponemes elicited distinct mechanisms of pathogenesis. and increased abundance of mRNA transcripts associated with apoptosis, while and increased transcripts involved in actin rearrangement and loss of cell adhesion, likely promoting tissue invasion. The upregulation of antimicrobial peptide precursor, DEFB123, by spirochaetes may present a microbial ecological advantage to all treponemes within BDD infected tissue, explaining their dominance within lesions. A commensal, , significantly dysregulated over three times the number of host mRNA transcripts compared to BDD treponemes, implying BDD treponemes, akin to the syphilis pathogen (), 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 fibroblast observations and highlighting the system's value in modeling BDD pathogenesis. Several unique shared gene targets were identified, particularly , , , and . The three key BDD 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.
牛传染性皮肤病（BDD）是一种常见的牛只趾间皮肤传染病，也是全球跛行的重要原因，目前治疗方法有限。它对动物福利和食品安全的全球关注日益增加，每年给养牛业带来巨大的经济负担。已经确定了一种多螺旋体病因，全球范围内有三个关键的系统发育群： 、 和 。能够实现靶向治疗/治疗开发的致病机制尚未得到明确界定。本研究使用 RNA 测序确定了在三种代表性 BDD 密螺旋体和一种共生密螺旋体 感染后，原发性牛足皮肤成纤维细胞中的全差分 mRNA 表达。BDD 密螺旋体通过 信号引发促炎反应。出乎意料的是，三种 BDD 密螺旋体引发了不同的发病机制。 和 增加了与细胞凋亡相关的 mRNA 转录物的丰度，而 和 增加了参与肌动蛋白重排和细胞黏附丧失的转录物，可能促进组织侵袭。 螺旋体上调抗菌肽前体 DEFB123，可能为 BDD 感染组织中的所有密螺旋体提供微生物生态优势，解释了它们在病变中的优势。一种共生密螺旋体 与 BDD 密螺旋体相比，其宿主 mRNA 转录物的失调超过三倍，这意味着 BDD 密螺旋体，类似于梅毒病原体（），已经进化为“隐形病原体”，它们避免引发宿主免疫/炎症反应，以保持持久性和组织侵袭。免疫组织化学显示 BDD 病变中 IL-6、IL-8、RND1 和 CFB 蛋白表达增加，证实了 成纤维细胞的观察结果，并强调了该系统在模拟 BDD 发病机制方面的价值。鉴定了几个独特的共享基因靶点，特别是 、 、 和 。这三个关键的 BDD 系统发育群在牛只足部皮肤中引发了既独特又共享的致病机制；在同时抑制适应性免疫的情况下上调炎症。这里鉴定的新基因靶点应该能够为未来的疫苗/治疗方法提供依据。
