A therapeutic for Lyme disease based on Peptidoglycan Recognition Protein 1

基于肽聚糖识别蛋白 1 的莱姆病治疗方法

基本信息

批准号：
10461961
负责人：
SUKANYA NARASIMHAN
金额：
$ 29.95万
依托单位：
L2 DIAGNOSTICS, LLC
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-04 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10461961
关键词：
Acute Adverse effects Adverse event Amoxicillin Antibiotic Therapy Antibiotics Arthritis Bacteria Binding Binding Proteins Borrelia Borrelia burgdorferi C3H/HeN Mouse Carditis Ceftriaxone Cell Wall Characteristics Clinical Combined Modality Therapy Distal Doxycycline Fever Formulation Future Goals Headache Health Heart Human Immunologic Receptors In Vitro Inbred BALB C Mice Infection Innate Immune Response Integration Host Factors Intravenous Joints Knockout Mice Libraries Lyme Arthritis Lyme Disease Measurable Measures Monobactams Mus Myalgia Nervous system structure North America Oral Order Spirochaetales Organ Outcome Parents Patients Peptides Peptidoglycan Peptidyltransferase Phase Property Recombinants Refractory Route Safety Skin Symptoms Synovitis Testing Tetracyclines Therapeutic Tissues Vaccines Vector-transmitted infectious disease Yeasts alternative treatment base clinically relevant cost effective cytokine dosage experimental study host microbiome improved in vitro activity in vivo mouse model novel strategies peptidoglycan recognition protein pharmacokinetics and pharmacodynamics phase 2 study prophylactic receptor response secretory protein tick bite

项目摘要

ABSTRACT Lyme disease, the most common vector-borne illness in North America, is caused by the spirochete B. burgdorferi. Infection begins in the skin following an infected tick-bite and acute illness is characterized by headache, fever and myalgia. Currently, there is no human vaccine against Lyme disease and therapeutic administration of antibiotics remains the recommended treatment option. In the absence of a recollection of a tick bite, or if the early symptoms go unnoticed and untreated the spirochete can disseminate to distal regions of the skin, heart, nervous system and the joints, leading to clinical manifestations of disseminated Lyme disease including carditis, neuroborreliosis and arthritis. The treatment option for early and late disseminated Lyme disease is also oral antibiotic treatment for 14-21 days or longer, or intravenous antibiotic administration. In North America, 60 % of untreated Lyme disease patients develop Lyme arthritis and up to 10 % of these patients demonstrate synovitis even after prolonged antibiotic treatment. Adverse events from prolonged antibiotic treatment, and the growing understanding of the importance of the host microbiome in health, emphasize the need to develop effective alternative treatment options for the control of Lyme disease. Towards this goal, this proposal will determine the utility of Peptidoglycan Recognition Protein 1 (PYGLRP1) to control Borrelia burgdorferi infection in a murine model of Lyme disease. Using a yeast display library expressing over 1000 human immune receptors and secretory proteins we examined molecular interactions between human immune receptors and B. burgdorferi and showed that a vast majority of strains of B. burgdorferi sensu stricto bind specifically to PGLYRP1. In-vitro experiments demonstrated that PGLYRP1 has borreliacidal activity. We hypothesize that PGLYRP1, a peptidoglycan-recognition protein, may be used by the host to recognize and eradicate B. burgdorferi. Consistent with our hypothesis, B. burgdorferi burden in mice lacking PGLYRP1 was increased compared to that in control mice. Therefore, in Aim 1 of this proposal, we will evaluate the potential of recombinant PGLYRP1 as a therapeutic to eradicate B. burgdorferi infection in a murine model of Lyme disease. In Aim 2 of this study we will determine whether PGLYRP1 acts synergistically with beta-lactam antibiotics such as ceftriaxone to prophylactically treat B. burgdorferi infection. The results of this study will provide the basis for future efforts that will define an optimal formulation of PGLYRP1 as a therapeutic for Lyme disease.

抽象的莱姆病是北美最常见的媒介传播疾病，由伯氏疏螺旋体螺旋体引起。被感染的蜱虫叮咬后，感染开始于皮肤，急性疾病的特点是头痛、发烧和肌痛。目前，还没有针对莱姆病的人类疫苗，抗生素治疗仍然是推荐的治疗选择。在不记得被蜱虫叮咬的情况下，或者如果早期症状未被注意到且未得到治疗，螺旋体可能会传播到皮肤、心脏、神经系统和关节的远端区域，导致播散性莱姆病的临床表现，包括心脏炎、神经疏螺旋体病和关节炎。早期和晚期播散性莱姆病的治疗选择也是口服抗生素治疗 14-21 天或更长时间，或静脉注射抗生素。在北美，60% 未经治疗的莱姆病患者会发展为莱姆关节炎，其中高达 10% 的患者即使在长期抗生素治疗后也会出现滑膜炎。长期抗生素治疗引起的不良事件，以及人们对宿主微生物组对健康重要性的日益了解，都强调需要开发有效的替代治疗方案来控制莱姆病。为了实现这一目标，该提案将确定肽聚糖识别蛋白 1 (PYGLRP1) 在莱姆病小鼠模型中控制伯氏疏螺旋体感染的效用。使用表达超过 1000 种人类免疫受体和分泌蛋白的酵母展示文库，我们检查了人类免疫受体和伯氏疏螺旋体之间的分子相互作用，并表明绝大多数伯氏疏螺旋体菌株与 PGLYRP1 特异性结合。体外实验证明 PGLYRP1 具有疏螺旋体酸活性。我们假设 PGLYRP1（一种肽聚糖识别蛋白）可能被宿主用来识别和根除伯氏疏螺旋体。与我们的假设一致，与对照小鼠相比，缺乏 PGLYRP1 的小鼠的伯氏疏螺旋体负荷增加。因此，在本提案的目标 1 中，我们将评估重组 PGLYRP1 作为根除莱姆病小鼠模型中的伯氏疏螺旋体感染的治疗剂的潜力。在本研究的目标 2 中，我们将确定 PGLYRP1 是否与 β-内酰胺抗生素（例如头孢曲松）协同作用来预防性治疗伯氏疏螺旋体感染。这项研究的结果将为未来确定 PGLYRP1 治疗莱姆病的最佳配方奠定基础。