Neutralization of Apx toxicity as an alternative to antibiotics for control of contagious porcine pleuropneumonia.

中和 Apx 毒性，作为抗生素的替代品，用于控制传染性猪胸膜肺炎。

• 批准号: MR/N01345X/1
• 负责人: Andrew Rycroft
• 金额: $ 29.82万
• 依托单位: Royal Veterinary College
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2016
• 资助国家: 英国
• 起止时间: 2016 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FN01345X%2F1
• 关键词: Neutralization; Apx; toxicity; alternative; antibiotics

Contagious pleuropneumonia is a severe acute disease that kills many growing pigs and causes lifelong damage to the lungs of those that survive. This impacts on the profitability of the production system. Pig farms regularly use antibiotics to control this disease because there is very little that can otherwise be used.Before the advising veterinary surgeon on a pig unit can reduce the use of antibiotics, we need alternatives for them to use. Apart from improving husbandry practices such as increasing ventilation and reducing the number of animals held together, there is little that can be offered. This is a problem throughout the world and is one of the primary reasons for using prescription antibiotics in pigs throughout Europe. In the UK, there is no effective vaccine because these have failed to protect pigs from disease, or the vaccine was itself toxic. Efforts to make on-farm vaccines (emergency vaccines) have not solved the problem because they are not efficacious and antibiotics, in feed, in water and by injection, are used in an attempt to avoid catastrophic losses.The disease is caused by a bacterium, Actinobacillus pleuroneumoniae, which produces two of three different protein toxins (ApxI, II and III). Production of these toxins by the pathogen is key to the disease process. Pigs that recover from disease have antibodies which neutralize the toxins and evidence suggests this is crucial in protecting pigs from the disease. It needs to be replicated in a successful vaccine. However, simply using the toxin(s) as a vaccine does not protect pigs. Despite stimulating production of antibodies these are not toxin-neutralizing antibodies. It appears that these bacteria have evolved to synthesise toxin molecules with irrelevant but highly immunogenic regions to distract the immune response to the wrong part of the toxin so that the antibody response is ineffective allowing the bacteria to spread and the disease continue.In this project we will eliminate those parts of the toxin that are distracting the immune response and which appear to be causing failure of the toxin molecules to generate a neutralizing response when used as a vaccine. These small fragments will be joined to a carrier protein, modified diphtheria toxin. This will enhance the immune response and make the antigen large enough to be recognised by the pigs' immune system as a vaccine antigen. We will immunize pigs with these modified toxins and measure the immune response and the neutralizing effect against the active toxins. To improve the method of testing the toxins and the effect of neutralizing antibody, we will develop and test a pig model of dermal oedema. This will be used to indicate the best vaccine antigens for use in the pig model of pleuropneumonia. We will then proceed to immunize pigs and test the efficacy of the vaccination by experimental challenge of the pigs with the virulent pathogen.If this hypothesis is correct, and the immune response to the toxin fragment is effective, this could be the step needed for production of an effective vaccination against pleuropneumonia and the opportunity, finally, to offer the pig industry an alternative to antibiotics which would markedly reduce the quantity of these drugs used in controlling pig respiratory disease.

传染性胸膜肺炎是一种严重的急性疾病，可导致许多生长猪死亡，并对存活猪的肺部造成终身损害。这将影响生产系统的盈利能力。养猪场经常使用抗生素来控制这种疾病，因为很少有其他方法可以使用。在为养猪单位提供建议的兽医减少使用抗生素之前，我们需要他们使用替代品。除了改善畜牧业的做法，如增加通风和减少动物的数量放在一起，有什么可以提供。这是一个世界性的问题，也是欧洲猪使用处方抗生素的主要原因之一。在英国，没有有效的疫苗，因为这些疫苗不能保护猪免受疾病的侵害，或者疫苗本身有毒。尽管人们努力研制农场疫苗（紧急疫苗），但这并没有解决问题，因为它们并不有效，为了避免灾难性的损失，人们在饲料、水中和注射中使用了抗生素。这种疾病是由一种细菌引起的，即胸膜炎放线杆菌（Actinobacillus pleuroneuminescent），它能产生三种不同蛋白质毒素（ApxI、II和III）中的两种。病原体产生这些毒素是疾病过程的关键。从疾病中恢复的猪具有中和毒素的抗体，证据表明这对保护猪免受疾病的影响至关重要。它需要在成功的疫苗中复制。然而，仅仅使用毒素作为疫苗并不能保护猪。尽管刺激抗体的产生，但这些抗体不是毒素中和抗体。这些细菌似乎已经进化到合成毒素分子，这些毒素分子具有不相关但高度免疫原性的区域，以将免疫反应分散到毒素的错误部分，使得抗体反应无效，从而允许细菌传播和疾病继续。在这个项目中，我们将消除毒素中那些分散免疫反应的部分，这些部分似乎导致毒素分子无法当用作疫苗时产生中和反应。这些小片段将连接到载体蛋白，修饰的白喉毒素。这将增强免疫反应，并使抗原足够大，以被猪的免疫系统识别为疫苗抗原。我们将用这些改良的毒素免疫猪，并测量免疫反应和对活性毒素的中和作用。为了改进毒素检测方法和中和抗体的效果，我们将建立和测试猪皮肤水肿模型。这将用于指示用于猪胸膜肺炎模型的最佳疫苗抗原。然后，我们将对猪进行免疫接种，并通过用强毒病原体对猪进行实验性攻击来测试疫苗接种的效力。如果这一假设是正确的，并且对毒素片段的免疫应答是有效的，那么这可能是生产针对胸膜肺炎的有效疫苗所需的步骤和机会，最后，为养猪业提供抗生素的替代品，从而显著减少用于控制猪呼吸道疾病的抗生素的用量。

项目成果

An Experimental Dermal Oedema Model for Apx Toxins of Actinobacillus pleuropneumoniae.

胸膜肺炎放线杆菌 Apx 毒素的实验性皮肤水肿模型。

• DOI: 10.1016/j.jcpa.2022.04.004
• 发表时间: 2022
• 期刊: Journal of comparative pathology
• 影响因子: 0.8
• 作者: Soutter F

Is the production of a Covid-19 vaccine using transformed Pasteurella plausible?

使用转化的巴斯德氏菌生产 Covid-19 疫苗是否可行？

• DOI: 10.1136/vr.m2423
• 发表时间: 2020
• 期刊: The Veterinary record
• 作者: Rycroft AN