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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

基本信息

批准号：
10674208
负责人：
Kevin Esvelt
金额：
$ 23.51万
依托单位：
MASSACHUSETTS INSTITUTE OF TECHNOLOGY
依托单位国家：
美国
项目类别：
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/10674208
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 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 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

项目摘要

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.

项目总结RFA-AI-19-037