Targeting iron acquisition for prevention of disease in ruminants

这项研究的重点是寄居在牛和其他反刍动物上呼吸道的细菌，这些细菌是呼吸道感染的主要原因，包括“运输热”，这仍然是养牛业面临的一个主要问题。虽然有许多疫苗用于预防这种感染，但它们并没有大大减少这个问题，主要是因为它们没有充分处理引起感染的细菌中的抗原变异。为了克服这个问题，我们计划利用所有这些细菌共有的共同特征，并最终从这些细菌共有的表面蛋白中开发出改进的疫苗抗原。我们提出的目标表面蛋白是从宿主铁结合蛋白转铁蛋白中获取生长所需铁的必需蛋白。我们的第一步是确定这些蛋白质在上呼吸道定植的病原体和相关细菌中的流行程度，并详细了解这些蛋白质的抗原多样性。这一点很重要的原因是，如果这些蛋白质存在于定植在上呼吸道的其他细菌中，它们可能会成为抗原变异的储存库，病原体可以利用这些变异来逃避疫苗。这些蛋白质序列的比较将通过我们小组确定的几个这些蛋白质的详细三维结构的可用性而增强。详细了解这些蛋白可变区域的位置和功能将为基于结构的蛋白工程开发具有更好免疫特性的抗原提供基础。我们还计划使用我们开发的新检测方法来评估免疫动物的血清对携带多种蛋白质抗原变体的菌株的保护能力。这些试验将有助于工程改进和优化疫苗抗原，并将提供一种相对廉价的方法来评估交叉保护疫苗的效果。

This study is focused on bacteria that colonize the upper respiratory tract of cattle and other ruminants and are the primary cause of respiratory infections, including ‘shipping fever’, which continues to be a major problem facing the cattle industry. Although there are a number of vaccines in use that are designed to prevent this infection, they have not substantially reduced the problem, primarily because they do not adequately deal with antigenic variation in the bacteria that cause the infection. To overcome this problem we plan to take advantage of a common trait that all these bacteria share, and ultimately develop improved vaccine antigens from the surface proteins that are common to these bacteria. The surface proteins that we propose to target are essential for acquiring iron for growth from the host iron binding protein, transferrin. Our first step is to determine the prevalence of these proteins in pathogens and related bacteria that colonize the upper respiratory tract and to obtain a detailed understanding of antigenic diversity of these proteins. The reason this is important is that if the proteins are present in other bacteria that colonize the upper respiratory tract, they may serve as a reservoir for antigenic variants that the pathogens could use to evade the vaccine. Comparison of the sequences of these proteins will be enhanced by the availability of the detailed three-dimensional structure of several of these proteins that our group has determined. The detailed understanding of the location and function of the variable regions of these proteins will provide the foundation for structure-based protein engineering for developing antigens with improved immunological properties. We also plan to use novel assays we developed to evaluate sera from immunized animals for their ability to protect against strains carrying the diverse set antigenic variants of the proteins. These assays will be useful for engineering improved and optimized vaccine antigens, and will provide a relatively inexpensive means of evaluating how cross-protective vaccines will be.