Section of Infectious Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, United States of America.
Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut, United States of America.
PLoS Pathog. 2020 Nov 11;16(11):e1009030. doi: 10.1371/journal.ppat.1009030. eCollection 2020 Nov.
Lyme disease, the most common vector-borne illness in North America, is caused by the spirochete Borrelia burgdorferi. Infection begins in the skin following a tick bite and can spread to the hearts, joints, nervous system, and other organs. Diverse host responses influence the level of B. burgdorferi infection in mice and humans. Using a systems biology approach, we examined potential molecular interactions between human extracellular and secreted proteins and B. burgdorferi. A yeast display library expressing 1031 human extracellular proteins was probed against 36 isolates of B. burgdorferi sensu lato. We found that human Peptidoglycan Recognition Protein 1 (PGLYRP1) interacted with the vast majority of B. burgdorferi isolates. In subsequent experiments, we demonstrated that recombinant PGLYRP1 interacts with purified B. burgdorferi peptidoglycan and exhibits borreliacidal activity, suggesting that vertebrate hosts may use PGLYRP1 to identify B. burgdorferi. We examined B. burgdorferi infection in mice lacking PGLYRP1 and observed an increased spirochete burden in the heart and joints, along with splenomegaly. Mice lacking PGLYRP1 also showed signs of immune dysregulation, including lower serum IgG levels and higher levels of IFNγ, CXCL9, and CXCL10.Taken together, our findings suggest that PGLYRP1 plays a role in the host's response to B. burgdorferi and further demonstrate the utility of expansive yeast display screening in capturing biologically relevant interactions between spirochetes and their hosts.
莱姆病是北美最常见的虫媒传染病，由螺旋体伯氏疏螺旋体引起。感染始于蜱叮咬后的皮肤，可传播至心脏、关节、神经系统和其他器官。宿主的多种反应影响着小鼠和人体内伯氏疏螺旋体的感染水平。我们采用系统生物学方法，研究了人类细胞外和分泌蛋白与伯氏疏螺旋体之间潜在的分子相互作用。一个表达 1031 个人类细胞外蛋白的酵母展示文库，被用来探测 36 株伯氏疏螺旋体属。我们发现人类肽聚糖识别蛋白 1（PGLYRP1）与绝大多数伯氏疏螺旋体属分离株相互作用。在随后的实验中，我们证明重组 PGLYRP1 与纯化的伯氏疏螺旋体肽聚糖相互作用，并表现出杀菌活性，这表明脊椎动物宿主可能利用 PGLYRP1 来识别伯氏疏螺旋体。我们在缺乏 PGLYRP1 的小鼠中研究了伯氏疏螺旋体的感染，观察到心脏和关节中的螺旋体负担增加，同时伴有脾肿大。缺乏 PGLYRP1 的小鼠还表现出免疫失调的迹象，包括血清 IgG 水平降低和 IFNγ、CXCL9 和 CXCL10 水平升高。综上所述，我们的研究结果表明，PGLYRP1 在宿主对伯氏疏螺旋体的反应中发挥作用，并进一步证明了广泛的酵母展示筛选在捕捉螺旋体与其宿主之间具有生物学意义的相互作用方面的实用性。
