Efficacy of novel reservoir-host targeted bait formulations against a tick-borne pathogen

新型储存宿主靶向诱饵制剂对抗蜱传病原体的功效

• 批准号: 10477926
• 负责人: Janakiram Seshu
• 金额: $ 37.5万
• 依托单位: UNIVERSITY OF TEXAS SAN ANTONIO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10477926
• 关键词: Adjuvant; Aftercare; Anti-Bacterial Agents; Antibiotics; Antibodies; Antigens; Area; Bite; Black-legged Tick; Borrelia; Borrelia burgdorferi; C3H/HeN Mouse; Carbon; Centers for Disease Control and Prevention (U.S.); Cues; Disease; Dose; Engineering; Escherichia coli; Formulation; Gene Expression Regulation; Genetic Engineering; Genetically Modified Organisms; Goals; Health Care Costs; Human; Immune response; Immunity; Immunization; Immunize; Incidence; Infection; Infectious Agent; Interruption; Larva; Life Cycle Stages; Lipoproteins; Lyme Disease; M cell; Membrane Proteins; Molecular Conformation; Morbidity - disease rate; Mus; Natural History; Nature; Nymph; Oral; Oral Administration; Order Spirochaetales; Organism; OspA protein; OspC protein; Patients; Peptides; Peromyscus; Prevention; Property; RNA-Binding Proteins; Recombinant Proteins; Reporting; Research; Route; Site; Surface; Symptoms; System; Testing; Tick-Borne Diseases; Ticks; Vaccinated; Vaccination; Vaccines; White-Footed Mouse; adaptive immune response; arthropod-borne; base; dosage; efficacy evaluation; enzootic; mouse model; mutant; novel; novel strategies; oral vaccine; parenteral administration; pathogen; pathogenic bacteria; prevent; public health relevance; reconstitution; response; tick-borne pathogen; tool; transmission process; treatment choice; vaccine access; vaccine development; vaccine platform; vector tick

Lyme disease is the most common tick-borne illness in the US. Currently, there are no vaccines available to prevent Lyme disease and antibacterial therapy is the treatment of choice. The disease is caused by a spirochete, Borrelia burgdorferi, which is maintained in nature through an enzootic cycle involving a tick vector and a variety of vertebrate hosts. Regulation of gene expression in B. burgdorferi in response to environmental cues prevalent in these highly divergent hosts is critical for pathogen survival and transmission between the tick vector and vertebrate hosts. Deletion of Borrelia host-adaptation Regulator (BadR) and site-specific replacement of 8 critical residues of Carbon Storage Regulator A result in dysregulated borrelial strains that hyper-express a variety of lipoproteins. Purified Borrelial Lipoproteins (PBLs) from these strains confer protection when administered via parenteral route against challenge with B. burgdorferi infected Ixodes scapularis nymphs. Consistent with the RFA-AI-19-037 “Targeted Prevention of Tickborne Diseases”, this proposal is directed at evaluating PBLs from hyper-expression borrelial mutants as a bait-formulation to develop a reservoir-targeted approach to interrupt the natural history of B. burgdorferi infection using experimental (C3H/HeN) and reservoir (Peromyscus leucopus, white-footed mouse) mouse models of Lyme disease. Use of PBLs in their native conformation circumvents the need to express these antigens as recombinant proteins in heterologous systems or limitations in their reconstitution to reflect their proportions on the borrelial surface. The central hypothesis of this proposal is that oral administration of PBLs protects reservoir hosts against Bb challenge via ticks and interferes with the natural history of infection via Ixodes scapularis ticks. This hypothesis will be tested with 3 specific aims. In Specific Aim 1, correlates of protective immunity induced by PBLs against B. burgdorferi will be determined. Humoral immune response, levels of borrelicidal antibodies and levels of protection against B. burgdorferi challenge via ticks induced in C3H/HeN or P. leucopus mice following oral or parenteral administration of PBLs will be compared. In Specific Aim 2, the levels of PBL-induced reduction in B. burgdorferi burden in ticks will be determined. The ability of naïve tick larvae and nymphs fed on PBL-immunized mice to acquire and transmit B. burgdorferi to naïve mice will be ascertained to establish a strategy to interfere with the natural history of infection. In Specific Aim 3, several adjuvants and novel strains of B. burgdorferi expressing lipoproteins with properties to increase the potency of a single dose, oral, reservoir bait vaccine will be evaluated. These studies are novel in exploiting the components of genetically defined borrelial mutants in conjunction with adjuvants that increase the potency of PBLs administered as bait formulations to interfere with natural life cycle of Lyme disease pathogen. Overall, the proposed strategies will help in developing a vaccine platform exploiting genetically modified avirulent organisms or their components to block one or more tick-borne pathogens.

莱姆病是美国最常见的扁虱传播疾病。目前，还没有疫苗可用来 预防莱姆病和抗菌治疗是首选的治疗方法。这种疾病是由一种 螺旋体，伯氏疏螺旋体，在自然界中通过涉及壁虱媒介的地方性循环而维持 以及各种脊椎动物宿主。伯氏杆菌基因表达调控对环境的响应 在这些高度分化的宿主中普遍存在的提示对于病原体的生存和在 壁虱媒介和脊椎动物宿主。疏螺旋体宿主适应调节因子(BadR)的缺失和位点特异性 碳储存调节剂A的8个关键残基的替换导致了失调的硼细菌菌株 超量表达多种脂蛋白。从这些菌株中纯化的疏螺旋体脂蛋白(PBL)提供 通过肠外途径给药对感染伯氏巴氏杆菌的攻击的保护作用 肩胛若虫。与RFA-AI-19-037《有针对性地预防壁虱传播疾病》一致， 该提案旨在评估来自高表达硼突变体的PBL作为诱饵制剂 开发一种针对水库的方法来中断伯氏杆菌感染的自然历史，使用 实验性(C3H/母鸡)和蓄积性(白斑Permyscus leucopus，白足小鼠)小鼠莱姆病模型 疾病。在其天然构象中使用PBL避免了将这些抗原表达为 异源系统中的重组蛋白或其重组中的限制以反映其在 渗硼的表面。这项提议的中心假设是口服PBL可以保护 水库通过扁虱寄主抵抗BB挑战，并干扰通过硬蜱感染的自然病史 肩骨扁虱。这一假设将通过三个具体目标进行检验。在具体目标1中，保护的相关因素 将确定PBL诱导的对伯氏杆菌的免疫力。体液免疫反应，水平 在C3H/母鸡或母鸡中诱导的抗伯氏杆菌攻击的边杀性抗体和保护水平 我们将比较口服或非肠道注射PBL后的白纹伊蚊小鼠。在具体目标2中， 将确定PBL诱导的勃氏假单胞菌在硬蜱中的负担减少程度。天真的扁虱的能力 以PBL免疫的小鼠为食的幼虫和若虫将获得伯氏杆菌并将其传播给幼鼠 确定了一项干预感染自然病史的策略。在具体目标3中，几个 表达脂蛋白的伯氏杆菌佐剂和新菌株具有增强脂蛋白效力的特性 将对单剂口服水库诱饵疫苗进行评估。这些研究在开发 基因定义的硼酸突变体的成分与佐剂相结合，可增加 用PBL作为诱饵制剂干扰莱姆病病原体的自然生活史。总的来说， 拟议的策略将有助于开发利用转基因无毒疫苗的疫苗平台 生物体或其成分，以阻止一种或多种壁虱传播的病原体。