sRNA-based therapeutics for disease caused by A. pleuropneumoniae

胸膜肺炎放线杆菌（APP）引起的细菌是一种高度传染性的猪肺病，影响英国和世界各地的猪群。感染导致快速死亡或缓慢生长，呼吸问题和痛苦。APP给全球养猪业造成了巨大的经济损失。在考虑到良好的饲养规范（提供良好的通风，全进/全出设施，避免温度波动和良好的卫生条件）后，有两种基本方法用于限制APP感染：即疫苗和抗生素。然而，目前的疫苗具有严重的局限性，抗生素耐药性越来越受到关注，最近的一项调查表明，英国70%的APP分离株现在对一种或多种抗生素具有耐药性。因此，迫切需要有效的治疗方法来对抗APP。解决这些问题直接符合BBSRC的关键战略优先事项“动物健康”，“管理动物的福利”和“对抗抗生素耐药性”。传统的抗生素寻求简单地杀死细菌，但一种新的治疗方法是靶向细菌感染宿主的能力所必需的功能。这种方法有效地解除了细菌的武装，而不是杀死它们，从而避免了传统抗生素耐药性起源的选择压力。细菌细胞，如APP，具有重要的开关分子（sRNAs），负责开启使宿主感染发生的机制。我们的提案计划在APP中识别这些关键的sRNA，然后使用称为肽核酸（PNAs）的化合物抑制它们的功能。以这种方式靶向sRNA将导致治疗APP疾病的新治疗方法。更广泛地说，这项研究还为探索sRNA抑制作为动物和人类其他主要病原体引起的细菌疾病的替代治疗方法提供了基础。这项工作是创新的，及时的和多学科的，建立在最近的工作基础上，采用最新的分子工具和技术进步来提供结果。这是一个联合合作企业，受益于APP（伦敦帝国理工学院伦敦）和sRNA研究（朴茨茅斯大学）的杰出记录之间的协同作用。在这种情况下，该项目有很大的成功机会，可以为治疗APP的能力提供一个台阶式的变化，但对更广泛的细菌性疾病的治疗具有深远的影响。

The bacterium Actinobacillus pleuropneumoniae (APP) causes is a highly contagious lung disease in pigs which affects herds in the UK and worldwide. Infection results in either rapid mortality or slow growth, breathing problems and suffering. APP is responsible for substantial economic losses to the worldwide pig industry.After good husbandry practices (provision of good ventilation, all in/all out facilities, avoidance of temperature fluctuations and good hygiene) are taken into account there are two basic methods used to limit APP infection: namely vaccines and antibiotics. However, current vaccines have severe limitations and antibiotic resistance is of increasing concern, a recent survey suggesting that 70% of APP isolates in the UK are now resistant to one or more antibiotics. Consequently, there is an urgent need for effective therapeutic approaches to combat APP. Addressing such issues directly aligns to the key BBSRC strategic priorities of 'Animal Health', 'Welfare of Managed Animals' and 'Combating Antimicrobial Resistance'.Traditional antibiotics seek to simply kill bacteria, but a novel therapeutic alternative is to target functions that are essential for the bacteria's ability to infect the host. Such an approach effectively disarms the bacteria, rather than killing them, thereby avoiding the selective pressure from which traditional antibiotic resistance originates. Bacterial cells, such as APP, have important switching molecules (sRNAs) which are responsible for turning on the mechanisms that enable host infection to occur. Our proposal plans to identify these crucial sRNAs in APP and then inhibit their function using compounds called peptide nucleic acids (PNAs). Targeting the sRNAs in this manner will lead to a new therapeutic approach for treating APP disease. More broadly, this research also provides the basis for exploring sRNA inhibition as an alternative therapeutic approach to bacterial diseases caused by other major pathogens of animals and man.This work is innovative, timely and multi-disciplinary, building on recent work and employing the latest molecular tools and technological advances to deliver results. This is a joint collaborative venture which benefits from the synergy between world leading expertise in APP (Imperial College London) and an outstanding track record in sRNA research (University of Portsmouth). Within this context, the project has a substantial chance of success, standing to offer a step change in capability for treating APP, but with far reaching impact for the therapeutic treatment of bacterial diseases more broadly.