Control of Campylobacter by CRISPR/CAS systems

农业面临许多重大和多样的挑战，包括需要在面对不断增长的世界人口的情况下满足提高生产率的需求，同时通过高度可持续地成为环境资源的有效保管者。就动物生产而言，实现这些全球目标，同时确保最高标准的健康和福利--顺便说一句，在影响人类健康的抗生素耐药性日益增强的当代背景下--必须依靠谨慎使用，如果不是“永远不使用抗生素”来维持动物健康。这是一个艰巨的目标，需要创新的、破坏性的新病原体控制措施。饲养禽肉是全球蛋白质生产增长最快的部门之一。虽然生物安全措施和一些饲料添加剂干预措施对禽类的健康和福利产生了影响，但人畜共患空肠弯曲菌仍然是一个重大的人类健康问题，家禽仍然是人类感染的主要来源。最新的政府数据显示，报告的病例数量从2016年的52,381例增加到2017年的56,729例，([https://www.gov.uk/government/publications/campylobacter-infection-annual-data/campylobacter-data-2008-to-2017][0])病例增加了4,348例，这一上升是尽管改善了农场和食物链的生物安全管理做法。这项提议的目的是完成一种新的颠覆性技术的开发，通过在生产水平上对家禽进行干预，为减少人类弯曲杆菌疾病做出贡献。到目前为止，Folium Science已经证明了通过将细菌免疫系统CRISPR-CAS系统重新定向为“自毁”来选择性地杀死沙门氏菌的能力。这一概念验证现正被开发用于商业释放，作为农场减少这种病原体负担的控制措施的一部分。第一个产品是一种成熟的益生菌，它携带CRISPR-CAS程序，以精致的特异性针对所有沙门氏菌血清型。益生菌将系统传递给沙门氏菌，诱导生长抑制。剩下的挑战是采用这项技术，并证明它可以重新编程以空肠弯曲菌为目标，虽然在家禽生长过程中对空肠弯曲菌几乎没有影响，但它是人类的主要病原体。在设计阶段，由于COVID19的原因，实验室关闭和工作人员休假中断了开发专门用于控制空肠弯曲菌的商业化前原型“引导生物”的工作方案。此应用程序旨在恢复该计划。设计已经完成了商业化前原型的步骤，包括(I)在没有任何脱靶效应的情况下验证目标的限制，(Ii)使用当前的益生菌递送系统进行递送。[0]：https://www.gov.uk/government/publications/campylobacter-infection-annual-data/campylobacter-data-2008-to-2017

Agriculture faces many major and diverse challenges including the need to meet the demand for increased productivity in the face of a growing world population whilst being effective custodians of environmental resources by being highly sustainable. For animal production, achieving these global goals whilst ensuring the highest standards of health and welfare, which incidentally in the contemporary context of growing antibiotic resistance impacting on human health, must rely upon prudent use if not "no use antibiotics ever" in maintaining animal health. This is a stretching aim that requires innovative, disruptive new pathogen control measures.Growing poultry for meat is one of the fastest growing sectors for protein production globally. Whilst biosecurity measures and some feed additive interventions impact on health and welfare of the birds, the human zoonotic _Campylobacter jejuni_ remains a significant human health issue with poultry still the primary source of human infections. The latest available government figures show reported number of cases increased from 52,381 in 2016 to 56,729 in 2017, an increase of 4,348 cases ([https://www.gov.uk/government/publications/campylobacter-infection-annual-data/campylobacter-data-2008-to-2017][0]) and this rise is despite improving biosecurity management practices on farm and through the food chain.The purpose of this proposal is to complete the development of a novel, disruptive technology to contribute to the reduction of Campylobacter illness in humans by interventions at production level, in poultry. To date, Folium Science has demonstrated the ability to selectively kill Salmonella by redirecting the bacterial immune system, the CRISPR-CAS system, to 'self-destruct'. This proof of concept is now being developed for commercial release as part of control measures on farm to reduce the burden of this pathogen. The first product is a well established probiotic that carries CRISPR-CAS programmed to target with exquisite specificity all Salmonella serotypes. The probiotic delivers the system to Salmonella inducing inhibition of growth.The challenge that remains is to take this technology and demonstrate that it can be reprogrammed to target _Campylobacter jejuni_ that, whilst having little effect in poultry as they grow, are major pathogens in humans. A programme of work to develop a pre-commercial prototype "Guided Biotic" specific for the control of _C. jejuni_ was interrupted at the design stage by laboratory closure and furlough of staff due to COVID19\. This application seeks to restore the programme. Having designs already made the steps to a pre-commercial prototype include (i) validation of restriction of the target without any off target effects, (ii) delivery using current probiotic delivery systems.[0]: https://www.gov.uk/government/publications/campylobacter-infection-annual-data/campylobacter-data-2008-to-2017