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: 10677804
• 负责人: Kevin Esvelt
• 金额: $ 88.1万
• 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/10677804
• 关键词: Adopted; Albumins; Alleles; Animals; Antibodies; Area; B-Lymphocytes; Back; Binding; Borrelia burgdorferi; Cell Line; 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; In Vitro; Incidence; Individual; Intervention; Investments; Light; Link; Liver; Lyme Disease; Methods; Midwestern United States; Mus; Mutation; OspA protein; Play; Population; Prevention; Prevention strategy; Production; Protective Clothing; Reciprocal Translocation; Recombinants; Research Personnel; Resistance; Risk; Role; Sorting; System; Testing; Tick-Borne Diseases; Ticks; Time; Transgenes; Transgenic Organisms; Vaccinated; White-Footed Mouse; Work; Zoonoses; acaricide; cost; disease transmission; embryonic stem cell; exposed human population; field study; fitness; in vitro activity; in vivo; interest; model organism; 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、美化环境和个人防护服， 必须定期重新使用、维护和佩戴。 老鼠对蜱虫 该项目旨在开发一种持久的一次性干预措施，以破坏生态环境， 莱姆病的传播周期长达数十年。莱姆病的病原体 疾病B。burgdorferi在蜱和它们的小动物宿主之间来回传播， 它们是人畜共患病的宿主。白足鼠P. leucopus广泛 被认为是最重要的水库，因为它既无处不在， 能够有效地通过蜱虫获取和传播病原体。我们的首要目标是 一个被提议的项目是通过编码一种基因， 保护性P 靶向B的白蛋白抗体。Burgdorferi外表面蛋白A（OspA） 小鼠生殖系根据我们的计算，结合至少四种这样的抗体应该 阻止了B的进化逃逸。burgdorferi因为太多的同时OspA突变 会被需要。至关重要的是，即使这些小鼠在某些领域的重要性不如目前 我认为，免疫接种会减少受感染的蜱虫数量，从而减少感染 次级储库，这将感染更少的蜱虫，加强负反馈螺旋 预计将大大减轻当地莱姆病的负担。我们已经成功地 从OspA免疫的P. leucopus，推测为P.白足 胚胎干细胞，并显示白蛋白位点似乎适合抗体分泌 从肝脏。我们现在寻求（1）鉴定结合至少四种不同OspA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） 产生遗传抗性小鼠，所述小鼠表达来自连接到 相互染色体易位，高阈值基因驱动的自然发生形式 这将使野生P的可逆和紧密定位的工程。白足 人口。我们的开放和社区指导的方法受到了明显的热情， 南图克特和玛莎葡萄园岛的居民，表明当地社区遭受 蜱传疾病在整个东北部和上中西部可能希望免疫他们的 几十年来，他们一直拥有野生小鼠种群，以帮助预防莱姆病。