A human secretome library screen reveals a role for Peptidoglycan Recognition Protein 1 in Lyme borreliosis.
A human secretome library screen reveals a role for Peptidoglycan Recognition Protein 1 in Lyme borreliosis.
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DOI：
10.1371/journal.ppat.1009030
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发表时间：
2020-11
期刊：
影响因子：
6.7
通讯作者：
Fikrig E
中科院分区：
文献类型：
--
作者：
Gupta A;Arora G;Rosen CE;Kloos Z;Cao Y;Cerny J;Sajid A;Hoornstra D;Golovchenko M;Rudenko N;Munderloh U;Hovius JW;Booth CJ;Jacobs-Wagner C;Palm NW;Ring AM;Fikrig E
莱姆病是北美最常见的病媒传播疾病，由伯氏疏螺旋体螺旋体引起。感染开始于蜱叮咬后的皮肤，并可扩散到心脏，关节，神经系统和其他器官。不同的寄主反应影响B的水平。小鼠和人类的伯氏螺旋体感染。使用系统生物学方法，我们研究了人类细胞外和分泌的蛋白质和B之间的潜在分子相互作用。burgdorferi。用酵母展示文库表达1031个人细胞外蛋白质，对36株B进行了检测。广义上的伯多禄我们发现人肽聚糖识别蛋白1（PGLYRP 1）与绝大多数B相互作用。伯氏分离物。在随后的实验中，我们证明了重组PGLYRP 1与纯化的B相互作用。表明PGLYRP 1可能是脊椎动物宿主识别B的有效途径。burgdorferi。我们检查了B。在缺乏PGLYRP 1的小鼠中观察到伯氏螺旋体感染，并观察到心脏和关节中螺旋体负荷增加，沿着脾肿大。PGLYRP 1缺失的小鼠也表现出免疫失调的迹象，包括较低的血清IgG水平和较高的IFNγ、CXCL 9和CXCL 10水平。综上所述，我们的研究结果表明PGLYRP 1在宿主对B的应答中起作用。burgdorferi的研究，并进一步证明了扩展酵母展示筛选在捕获螺旋体与其宿主之间的生物相关相互作用中的实用性。莱姆病是北美最常见的病媒传播疾病，由伯氏疏螺旋体螺旋体引起。这种疾病始于蜱虫叮咬，导致皮疹和身体其他器官的炎症，如心脏和关节。B。burgdorferi使用许多策略来逃避检测并在人类宿主中持续存在。重要的是要有有效的方法，能够识别与B相互作用的免疫系统的各种成分。burgdorferi，以更好地了解疾病的过程，但目前很少存在。在这项研究中，我们使用了一种新的酵母展示筛选试验，检测了1,000多种针对几种疏螺旋体分离株的人类免疫蛋白，以揭示莱姆病病原体的生物相关相互作用。我们确定了肽聚糖识别蛋白1（PGLYRP 1），一种在防御细菌方面很重要的先天免疫蛋白，作为该筛选的主要候选物。我们验证了PGLYRP 1与疏螺旋体的相互作用，并能够使用PGLYRP 1缺陷小鼠作为模型，以了解这种蛋白质在莱姆病发病机制中的作用。我们的研究表明了酵母筛选在揭示重要的宿主-病原体相互作用方面的潜在意义。
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. Lyme disease is the most common vector-borne illness in North America and is caused by the spirochete Borrelia burgdorferi. The disease starts with a tick bite that leads to a skin rash and inflammation in other organs of the body, such as hearts and joints. B. burgdorferi uses many strategies to evade detection and persist in the human host. It is important to have efficient methods to be able to identify the various components of the immune system that interact with B. burgdorferi to better understand the disease process, but few currently exist. In this study, we used a novel yeast display screening assay of over 1,000 human immune proteins probed against several isolates of Borrelia to uncover biologically relevant interactions for the Lyme disease pathogen. We identified Peptidoglycan Recognition Protein 1 (PGLYRP1), an innate immune protein important in defense against bacteria, as a major candidate from this screen. We validated the interaction of PGLYRP1 with Borrelia and were able to use PGLYRP1-deficient mice as a model to understand the role of this protein in Lyme disease pathogenesis. Our study demonstrates the potential implications of yeast screens in uncovering important host-pathogen interactions.
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影响因子：
82.9
作者：
Kashyap, Des Raj;Wang, Minhui;Dziarski, Roman
通讯作者：
Dziarski, Roman
影响因子：
3.2
作者：
Dowdell, Alexander S.;Murphy, Maxwell D.;Zuckert, Wolfram R.
通讯作者：
Zuckert, Wolfram R.
DOI：
10.1073/pnas.0407856101
发表时间：
2004-12-07
影响因子：
11.1
作者：
Guan, RJ;Roychowdhury, A;Mariuzza, RA
通讯作者：
Mariuzza, RA
肽聚糖识别蛋白（PGRP）。
影响因子：
12.3
作者：
Dziarski, Roman;Gupta, Dipika
通讯作者：
Gupta, Dipika
DOI：
10.1073/pnas.1610805113
发表时间：
2016-08-16
影响因子：
11.1
作者：
Jutras, Brandon Lyon;Scott, Molly;Jacobs-Wagner, Christine
通讯作者：
Jacobs-Wagner, Christine