Defining the role of post-translational regulation by extracellular proteases in the pathogenesis of Staphylococcus aureus osteomyelitis

确定细胞外蛋白酶翻译后调节在金黄色葡萄球菌骨髓炎发病机制中的作用

基本信息

批准号：
10379698
负责人：
MARK S SMELTZER
金额：
$ 45.18万
依托单位：
UNIV OF ARKANSAS FOR MED SCIS
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-06-15 至 2026-08-31
项目状态：
未结题

项目摘要

SUMMARY ABSTRACT We have demonstrated that mutation of the staphylococcal accessory regulatory (sarA) in Staphylococcus aureus results in an increase in the production of extracellular proteases to a degree that limits biofilm formation, limits cytotoxicity for mammalian cells including osteoblasts and osteoclasts, and limits the accumulation of both surface-associated and extracellular virulence factors. We have also demonstrated that this can be correlated with decreased virulence in animal models of sepsis and osteomyelitis. Moreover, we have confirmed that all of these phenotypes are evident in diverse clinical isolates of S. aureus and that they can be reversed by eliminating the ability of sarA mutants to produce extracellular proteases. In this proposal, we will expand on these observations to identify the specific extracellular proteases that are most relevant in the context of our underlying scientific hypothesis in diverse clinical isolates of S. aureus (Aim 1) and use the information gained to interrogate the impact of these proteases on the virulence factor repertoire on these clinical isolates, define the impact sarA and these proteases on bone remodeling and the host response in bone infection, and ultimately identify and evaluate the contribution of specific S. aureus virulence factors alone and in combination with each other on these phenotypes (Aim 2).

摘要摘要我们已经证明了葡萄球菌中葡萄球菌辅助调节（SARA）的突变金黄色葡萄球菌导致细胞外蛋白酶的产生增加到限制生物膜的程度形成，限制了包括成骨细胞和破骨细胞在内的哺乳动物细胞的细胞毒性，并限制了限制表面相关和细胞外毒力因子的积累。我们还证明了这可能与败血症和骨髓炎动物模型中的毒力降低相关。而且，我们已经证实，所有这些表型在金黄色葡萄球菌的各种临床分离株中都是显而易见的，并且它们是可以通过消除萨拉突变体产生细胞外蛋白酶的能力来逆转。在此提案中，我们将扩展这些观察结果，以确定最相关的特定细胞外蛋白酶我们基本的科学假设在金黄色葡萄球菌的各种临床分离株中的背景（AIM 1），并使用获得的信息是为了询问这些蛋白酶对毒力因子库对这些蛋白质的影响临床分离株，定义SARA的影响，这些蛋白酶对骨头重塑以及宿主反应骨骼感染，最终仅识别和评估特定金黄色葡萄球菌毒力因子的贡献并在这些表型上相互结合（AIM 2）。