Targeting iron acquisition for prevention of disease in ruminants

这项研究的重点是定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，包括仍然是养牛业面临的主要问题的运输热。虽然目前使用的一些疫苗旨在预防这种感染，但它们并没有实质上减少问题，主要是因为它们没有充分处理导致感染的细菌中的抗原变异。为了解决这个问题，我们计划利用所有这些细菌都有的一个共同特征，并最终从这些细菌共同的表面蛋白中开发出改进的疫苗抗原。我们建议针对的表面蛋白是从宿主铁结合蛋白转铁蛋白中获取铁以供生长所必需的。我们的第一步是确定这些蛋白在定植于上呼吸道的病原体和相关细菌中的流行率，并详细了解这些蛋白的抗原多样性。这一点很重要的原因是，如果这些蛋白质存在于其他定居在上呼吸道的细菌中，它们可能会成为病原体用来逃避疫苗的抗原变体的储存库。通过我们小组确定的几种蛋白质的详细三维结构的可用性，这些蛋白质的序列比较将得到加强。对这些蛋白质可变区位置和功能的详细了解将为基于结构的蛋白质工程开发具有更好免疫学特性的抗原奠定基础。我们还计划使用我们开发的新方法来评估免疫动物的血清对携带不同组蛋白抗原变体的菌株的保护能力。这些检测将有助于设计改进和优化的疫苗抗原，并将提供一种相对便宜的手段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.