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Exploitation of virulent/avirulent strain comparison to detect pathogen & host factors critical to the pathogenesis of bovine mastitis due to S.uberis

利用强毒/无毒菌株比较来检测病原体

基本信息

批准号：
BB/E018114/1
负责人：
Tracey Coffey
金额：
$ 55.64万
依托单位：
The Pirbright Institute
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2008
资助国家：
英国
起止时间：
2008 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=BB%2FE018114%2F1
关键词：
Exploitation virulent avirulent strain comparison

项目摘要

Bacterial infection of the udder of dairy cows results in a disease named mastitis. This disease is the most common infectious disease in farmed animals; around one million cases occur each year in the UK. Mastitis occurs in all milk producing species; it is painful, occasionally life threatening and results in the loss of milk production or the production of milk that is unfit for human consumption. The disease is currently controlled only by the rigorous attention to the hygiene of dairy cows and the large scale use of antibiotics. Despite these measures cattle still become infected. Now, rather than the infection spreading from cow to cow, infection comes only from sources of bacteria in the environment (fields, straw bedding etc). One bacterium which is a common cause of this disease world wide and which is often present in high numbers in the environment is Streptococcus uberis (Strep uberis). In this research project we intend to identify parts of the Strep uberis that allows it to infect the cow's udder and in so doing identify those parts of the bacterium that should be used to make effective vaccines. We will do this by comparing versions of this bacterium that are able to cause disease (virulent) with others that cannot (avirulent). We will identify the differences between virulent and avirulent Strep uberis, in some instances, by comparing all the genes present in each and looking for those which occur only in the virulent type. In other instances, we will identify the proteins that virulent Strep uberis have on their surface and release into their surroundings and see which ones are missing from the avirulent Strep uberis. By identifying proteins that are produced only by the virulent type we will be able to produce a list of proteins that may have a part to play in causing this disease. Each protein we identify is produced from a single gene in Strep uberis; therefore we can determine which proteins are essential to cause mastitis by inactivating the gene that produces the particular protein and asking the question: Is the new form of Strep uberis, lacking that particular gene/protein, still able to cause disease? To do this we have to try and infect dairy cattle with the new form of the bacterium. This is done under strictly monitored conditions to ensure that we use the least number of animals possible to obtain the correct results. We will be able to identify a number of proteins from Strep uberis that are essential for disease and these will become components of vaccines to prevent this painful condition. We also intend to use the virulent and avirulent types of Strep uberis to help us identify what happens during disease and to identify any parts of the immune response of the dairy cow that can be altered to prevent disease. After infection with bacteria, animals including humans respond by producing messages in the form of chemicals. These are responsible for the way the infected animal responds to that infection and can result in many features associated with the disease. In the case of mastitis, these chemical messages are responsible such things as attracting specific types of white blood cells from the circulating blood into the mammary gland and for inducing the swelling that leads to pain associated the disease. However, we do not understand which messages control which parts of the response and therefore we do not know which ones are helpful to the control of disease and which contribute to the disease itself. As we now have the possibility of creating infections with avirulent Strep uberis, which do not subsequently result in disease, we can compare the messages produced by the host in response to both virulent and avirulent types of this bacterium. The differences will allow us to identify which responses are associated with disease and which are not. This information could subsequently be used to develop drugs that interfere with the chemical messages and reduce the level of disease.

奶牛乳房的细菌感染会导致一种叫做乳腺炎的疾病。该病是养殖动物中最常见的传染病；英国每年大约有100万例病例。乳腺炎发生在所有产乳物种中；它是痛苦的，有时会危及生命，并导致牛奶产量下降或生产出不适合人类食用的牛奶。目前只能通过严格注意奶牛的卫生和大规模使用抗生素来控制这种疾病。尽管采取了这些措施，牛仍然会被感染。现在，感染不是在奶牛之间传播，而是只来自环境中的细菌来源（田地、稻草垫料等）。在世界范围内引起这种疾病的一种常见细菌是ubercoccus uberis（链球菌uberis），它在环境中经常大量存在。在这个研究项目中，我们打算确定结核菌感染奶牛乳房的部分，从而确定应该用来制造有效疫苗的细菌的部分。我们将通过比较这种细菌能够致病（有毒性）和其他不能致病（无毒性）的版本来做到这一点。在某些情况下，我们将通过比较每一种链球菌中存在的所有基因并寻找仅发生在毒性类型中的基因来确定毒性和无毒性链球菌之间的差异。在其他情况下，我们将识别有毒的结核菌表面上的蛋白质，并将其释放到周围环境中，看看无毒的结核菌中缺失了哪些蛋白质。通过识别仅由毒性类型产生的蛋白质，我们将能够产生一系列可能在导致这种疾病中起作用的蛋白质。我们鉴定的每一种蛋白质都是由链球菌的单一基因产生的；因此，我们可以通过灭活产生特定蛋白质的基因来确定哪些蛋白质是导致乳腺炎所必需的，并提出一个问题：缺乏特定基因/蛋白质的新形式的结核菌是否仍然能够引起疾病？要做到这一点，我们必须尝试用这种新型细菌感染奶牛。这是在严格监控的条件下进行的，以确保我们使用尽可能少的动物来获得正确的结果。我们将能够从链球菌中鉴定出许多对疾病至关重要的蛋白质，这些蛋白质将成为预防这种痛苦状况的疫苗的组成部分。我们还打算使用强毒性和无毒性的链球菌类型来帮助我们确定疾病期间发生的情况，并确定奶牛免疫反应的任何部分可以改变以预防疾病。在感染细菌后，包括人类在内的动物会以化学物质的形式产生信息。它们决定了受感染动物对感染的反应方式，并可能导致与该疾病相关的许多特征。在乳腺炎的情况下，这些化学信息负责将循环血液中的特定类型的白细胞吸引到乳腺中，并诱导肿胀，导致与疾病相关的疼痛。然而，我们不知道哪些信息控制着反应的哪些部分，因此我们不知道哪些信息有助于控制疾病，哪些信息有助于疾病本身。由于我们现在有可能用无毒的结核菌感染，而这种感染随后不会导致疾病，我们可以比较宿主对这种细菌的毒性和无毒性类型所产生的信息。这些差异将使我们能够确定哪些反应与疾病有关，哪些与疾病无关。这些信息随后可用于开发干扰化学信息并降低疾病水平的药物。