Heritable immunization of the white-footed mouse reservoir of Lyme disease

白足小鼠莱姆病储库的遗传免疫

• 批准号: 9989482
• 负责人: Kevin Esvelt
• 金额: $ 95.75万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 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/9989482
• 关键词: Adopted; Albumins; Alleles; Animal Model; Animals; Antibodies; Area; B-Lymphocytes; Back; Binding; Borrelia burgdorferi; Cell Line; Cell Surface Proteins; Chromosomal translocation; Communities; Deer; Disadvantaged; Disease; Disease Reservoirs; ES Cell Line; Elements; Engineering; Enterobacteria phage P1 Cre recombinase; Environment; Epitopes; Feedback; Gene Transfer Techniques; Genes; Geography; Goals; Heritability; Immunity; Immunization; Immunize; Immunoglobulin Variable Region; In Vitro; Incidence; Individual; Intervention; Investments; Light; Link; Liver; Lyme Disease; Membrane Proteins; Methods; Midwestern United States; Mus; Mutation; OspA protein; Play; Population; Prevention; Prevention strategy; Production; Protective Clothing; Reciprocal Translocation; Recombinants; Research Personnel; Resistance; Risk; Role; System; Testing; Tick-Borne Diseases; Ticks; Time; Transgenes; Transgenic Organisms; Vaccinated; White-Footed Mouse; Work; Zoonoses; acaricide; antibody test; cost; disease transmission; embryonic stem cell; exposed human population; field study; fitness; in vitro activity; in vivo; interest; pathogen; prevent; resistance gene; transmission process; underdominance

Project Summary ​ ​ RFA-AI-19-037 The rising incidence of Lyme disease demands new strategies for prevention. Existing methods such as acaricides, deer reduction, landscaping, and personal protective clothing, are inherently short-term and must be regularly re-applied, maintained and worn. ​The Mice Against Ticks project seeks to develop a durable one-time intervention to disrupt the ecological cycle of Lyme disease transmission for many decades​. The causative agent of Lyme disease ​B. burgdorferi ​is passed back and forth between ticks and their small animal hosts, which serve as zoonotic reservoirs of disease. The white-footed mouse ​P. leucopus​ is widely considered to be the most important reservoir because it is both ubiquitous and extremely efficient at acquiring and transmitting pathogens via ticks. Our overarching goal for this proposed project is to heritably immunize white-footed mice against Lyme by encoding protective ​P​. ​leucopus​ antibodies targeting ​B. burgdorferi ​outer surface protein A (OspA) in the mouse germline. According to our calculations, combining at least four such antibodies should prevent evolutionary escape by ​B. burgdorferi ​because too many simultaneous OspA mutations would be needed. Crucially, even if these mice are less important in some areas than currently thought, immunization will reduce the number of infected ticks, which in turn will infect fewer secondary reservoirs, which will infect fewer ticks, reinforcing a negative feedback spiral anticipated to greatly reduce the local burden of Lyme disease. We have already successfully isolated anti-OspA antibodies from OspA-immunized ​P. leucopus​, derived putative ​P. leucopus embryonic stem cells, and shown that the albumin locus appears suitable for antibody secretion from the liver. We now seek to (1) identify antibodies that bind to at least four different OspA epitopes, (2) establish a stable embryonic stem cell line and perform germline editing, and (3) generate heritably resistant mice that express antibodies from a cisgenic cassette linked to a reciprocal chromosomal translocation, a naturally occurring form of high-threshold gene drive that would enable the reversible and tightly localized engineering of wild ​P. leucopus populations. Our open and community-guided approach has met with apparent enthusiasm by residents of Nantucket and Martha’s Vineyard, indicating that local communities suffering from tick-borne disease throughout the Northeast and Upper Midwest may wish to immunize their own wild mouse populations in order to help prevent Lyme disease for many decades.

项目摘要​​RFA-AI-19-037 莱姆病发病率的上升需要新的预防策略。现有方法 例如杀螨剂、减少鹿、景观美化和个人防护服等，本质上是 短期使用，必须定期重新涂抹、维护和佩戴。老鼠对抗蜱虫 该项目旨在开发一种持久的一次性干预措施来破坏生态 莱姆病的传播周期长达数十年​。莱姆病的病原体 疾病​B.伯氏疏螺旋体​在蜱虫和它们的小动物宿主之间来回传播， 它们是人畜共患疾病的储存库。白足鼠​P. leucopus​广泛 被认为是最重要的水库，因为它无处不在且极为重要 通过蜱有效获取和传播病原体。我们的总体目标 拟议的项目是通过编码对白足小鼠进行遗传性免疫莱姆病 保护​P​。​白细胞​抗体针对​B.伯氏疏螺旋体​外表面蛋白 A (OspA) 小鼠种系。根据我们的计算，结合至少四种这样的抗体应该 防止进化逃逸 B.伯氏疏螺旋体​因为同时发生太多 OspA 突变 将需要。至关重要的是，即使这些老鼠在某些领域的重要性不如现在 人们认为，免疫接种会减少受感染蜱虫的数量，从而减少感染蜱虫的数量 次要宿主，将感染更少的蜱虫，强化负反馈螺旋 预计将大大减轻当地莱姆病的负担。我们已经成功 从 OspA 免疫的 P. 中分离出抗 OspA 抗体。 leucopus​，衍生推定​P.白斑 胚胎干细胞，并表明白蛋白位点似乎适合抗体分泌 来自肝脏。我们现在寻求 (1) 鉴定与至少四种不同 OspA 结合的抗体 表位，(2) 建立稳定的胚胎干细胞系并进行种系编辑，以及 (3) 产生具有遗传抗性的小鼠，这些小鼠表达来自与 染色体相互易位，一种自然发生的高阈值基因驱动形式 这将使野生 P. 的可逆且紧密定位的工程成为可能。白斑 人口。我们的开放和社区引导的方法受到了明显的热情 楠塔基特岛和玛莎葡萄园岛的居民，表明当地社区遭受 整个东北部和中西部北部地区的蜱传疾病可能希望对其进行免疫接种 几十年来，我们一直在培育自己的野生小鼠种群，以帮助预防莱姆病。