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

• 批准号: 10256453
• 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
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-04 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10256453
• 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

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.

摘要 莱姆病是北美最常见的病媒传播疾病，由螺旋体B引起。burgdorferi。感染开始于皮肤后，感染蜱叮咬和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，抗生素的治疗性给药仍然是推荐的治疗选择。在没有蜱叮咬的记忆，或者如果早期症状被忽视和未经治疗，螺旋体可以传播到皮肤，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%的未经治疗的莱姆病患者发展为莱姆病关节炎，其中高达10%的患者即使在长期抗生素治疗后也表现出滑膜炎。长期抗生素治疗引起的不良事件，以及对宿主微生物组在健康中重要性的日益认识，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（PYGLRP 1）的效用，以控制莱姆病小鼠模型中的伯氏疏螺旋体感染。 使用酵母展示文库表达超过1000人免疫受体和分泌蛋白，我们研究了人免疫受体和B之间的分子相互作用。结果表明，绝大多数菌株为B.严格意义上的burgdorferi特异性结合PGLYRP 1。体外实验证明PGLYRP 1具有杀疏螺旋体活性。我们假设PGLYRP 1是一种肽聚糖识别蛋白，可能被宿主用来识别和根除B。burgdorferi。与我们的假设一致，B。与对照小鼠相比，缺乏PGLYRP 1的小鼠中的伯氏螺旋体负荷增加。因此，在本提案的目的1中，我们将评估重组PGLYRP 1作为根除B的治疗剂的潜力。莱姆病小鼠模型中的伯氏螺旋体感染。在本研究的目的2中，我们将确定PGLYRP 1是否与β-内酰胺类抗生素如头孢曲松协同作用，以治疗B。伯氏感染这项研究的结果将为未来的努力提供基础，这些努力将确定PGLYRP 1作为莱姆病治疗剂的最佳配方。