Challenge of Bovine Foot Skin Fibroblasts With Digital Dermatitis Treponemes Identifies Distinct Pathogenic Mechanisms.
Challenge of Bovine Foot Skin Fibroblasts With Digital Dermatitis Treponemes Identifies Distinct Pathogenic Mechanisms.
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DOI：
10.3389/fcimb.2020.538591
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发表时间：
2020
影响因子：
5.7
通讯作者：
Evans NJ
中科院分区：
文献类型：
--
作者：
Newbrook K;Carter SD;Crosby-Durrani H;Evans NJ
牛指端皮炎(BDD)是牛指端皮肤的一种常见传染病，也是全球范围内导致跛行的重要原因，治疗方案有限。它日益引起全球对动物福利和粮食安全的关注，每年给养牛业带来巨大的经济负担。多发性梅毒的病原学一直被确认，全球涉及三个关键的系统群：中密螺旋体、噬菌密螺旋体和足密螺旋体。可能实现靶向治疗/治疗发展的致病机制尚未明确。本研究利用RNA测序技术检测了三种典型的BDD密螺旋体和一种共生密螺旋体反义密螺旋体对原代牛足皮肤成纤维细胞的整体差异表达。BDD密螺旋体通过IL-8/IL-17信号转导诱导促炎反应。出乎意料的是，这三种BDD密螺旋体引发了不同的致病机制。吞噬毛滴虫和足形毛滴虫增加了与细胞凋亡相关的mRNA转录本的丰度，而中型毛滴虫和足形毛滴虫增加了涉及肌动蛋白重排和细胞黏附丧失的转录本，可能促进了组织的侵袭。吞噬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了微生物生态优势，解释了它们在病变中的优势。与BDD密螺旋体相比，一种共生的瘤胃旋毛虫的宿主mRNA转录本数量显著失调三倍以上，这意味着BDD密螺旋体，类似于梅毒病原体(梅毒螺旋体)，已进化为“隐形病原体”，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。免疫组织化学显示BDD皮损中IL-6、IL-8、RND1和CFB蛋白表达增加，证实了体外成纤维细胞的观察结果，并强调了该系统在BDD发病机制模拟中的价值。确定了几个独特的共享基因靶点，特别是Rgs16、GRO1、MAFf和ZC3H12A。三个关键的BDD密螺旋体系统群在牛足皮肤中引发了不同的和共同的致病机制；在上调炎症的同时抑制适应性免疫。这里确定的新的基因靶点应该会使未来的疫苗/治疗方法成为可能。
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.
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影响因子：
3.1
作者：
BAEHNI, PC;SONG, M;ELLEN, RP
通讯作者：
ELLEN, RP
影响因子：
1.8
作者：
Caswell, JL;Middleton, DM;Gordon, JR
通讯作者：
Gordon, JR
影响因子：
3.7
作者：
Aspenström, P
通讯作者：
Aspenström, P
影响因子：
11.4
作者：
Fullner, KJ;Mekalanos, JJ
通讯作者：
Mekalanos, JJ
影响因子：
14.2
作者：
Eddleston, Jane;Herschbach, Jack;Zuraw, Bruce L.
通讯作者：
Zuraw, Bruce L.