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蜱传播疾病。目前，没有疫苗可用于 预防莱姆病和抗菌治疗是治疗的首选。这种疾病是由一种 螺旋体，伯氏疏螺旋体，通过涉及蜱媒介的地方病循环在自然界中维持 和各种脊椎动物宿主。B中基因表达的调节。Burgdorferi回应环境 在这些高度分化的宿主中普遍存在的线索对于病原体的存活和在宿主之间的传播是至关重要的。 蜱媒和脊椎动物宿主。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疏螺旋体菌株失调， 高表达多种脂蛋白。从这些菌株纯化的疏螺旋体脂蛋白（PBL）赋予 当通过肠胃外途径给药时，对B激发的保护作用。伯氏硬蜱感染 肩胛肌与RFA-AI-19-037“蜱传疾病的靶向预防”一致， 一项提案旨在评估来自高表达疏螺旋体突变体的PBL作为诱饵制剂， 开发一种靶向的方法来中断B的自然史。伯氏菌感染 莱姆病实验（C3 H/HeN）和储库（白足鼠，白足鼠）小鼠模型 疾病以其天然构象使用PBL避免了表达这些抗原的需要， 在异源系统中的重组蛋白或其重构中的限制，以反映它们在 疏螺旋体表面。这一建议的中心假设是，口服PBL可保护 通过蜱虫抵抗Bb攻击的储存宿主，并通过硬蜱干扰感染的自然史 肩胛肌蜱虫将通过3个具体目标对该假设进行检验。在具体目标1中， 由PBL诱导的抗B的免疫。伯多菲力会下定决心的。体液免疫反应， 杀疏螺旋体抗体和针对B的保护水平。通过在C3 H/HeN中诱导的蜱进行伯氏螺旋体攻毒，或 P.将比较口服或肠胃外施用PBL后的白瘤小鼠。具体目标2 PBL诱导的B减少水平。将测定蜱中的伯氏菌负荷。天真蜱的能力 以PBL免疫的小鼠作为宿主，获得并传播B。burgdorferi幼稚的小鼠将 确定建立干预感染自然史的策略。在具体目标3中， 佐剂和B的新菌株。表达具有增加 将评价单剂量口服储库诱饵疫苗。这些研究在利用 基因确定的疏螺旋体突变体的组分与佐剂结合， PBL作为诱饵制剂施用以干扰莱姆病病原体的自然生命周期。总的来说， 所提出的策略将有助于开发一种利用转基因无毒的疫苗平台， 生物体或其组分以阻断一种或多种蜱传病原体。