Heritable Immunization Establishes a New Model for Pathogen Control

Buchthal, J.; Chory, E. J.; Hill, Z.; Zhou, Y.; Bondage, D.; DeAmelio, S.; Freeman, J.; Jaenisch, R.; Markoulaki, S.; Marasco, W. A.; Telford, S.; Esvelt, K. M.

doi:10.1101/2024.12.19.629026

bioRxiv · 10.1101/2024.12.19.629026

Heritable Immunization Establishes a New Model for Pathogen Control

Buchthal, J.·Chory, E. J.·Hill, Z.·Zhou, Y.·Bondage, D.·DeAmelio, S.·Freeman, J.·Jaenisch, R.·Markoulaki, S.·Marasco, W. A.·Telford, S.·Esvelt, K. M.

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Abstract

Heritable immunization represents a promising approach for controlling infectious diseases by embedding immunity directly into the genomes of wild species that spread human pathogens. Here, we report the genetic engineering of Mus musculus to produce a neutralizing, protective single-chain antibody against Borrelia burgdorferi, the causative agent of Lyme disease. Engineered mice stably produced a LA-2 scFv-albumin fusion protein across multiple generations, demonstrating robust heritability and stability of gene expression. Following sequential challenges with infected and uninfected ticks, heterozygous mice exhibited strong resistance to infection, effectively interrupting the Borrelia burgdorferi disease transmission cycle. Having recently established novel protocols to genetically engineer the white-footed mouse, Peromyscus leucopus, a key reservoir of Lyme disease, these findings demonstrate the feasibility of heritable immunization as a potential strategy for mitigating Lyme disease transmission in the environment. More broadly, engineered reservoir immunity may offer a generalizable approach to controlling vector-borne and zoonotic disease with profound potential to improve human health.

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Buchthal, J., Chory, E. J., Hill, Z., Zhou, Y., Bondage, D., DeAmelio, S., Freeman, J., Jaenisch, R., Markoulaki, S., Marasco, W. A., Telford, S., Esvelt, K. M.. 2024-12-22. Heritable Immunization Establishes a New Model for Pathogen Control. https://doi.org/10.1101/2024.12.19.629026

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