A Regulatory Cascade that Controls Pneumococcal Capsule Biosynthesis

项目摘要 肺炎链球菌是世界上最令人衰弱的人类病原体之一，在美国是最严重的 社区获得性细菌性肺炎的常见原因，尽管有可用的疫苗。作为 疫苗只能包含免疫所需的部分毒株，我们必须找到替代疗法 瞄准这种致命病原体的所有93个不同版本(或血清型)。最大的问题之一是 肺炎球菌的研究正在了解这种病原体如何迅速从无害的鼻腔 与侵袭性病原体共生。理解这一关键转变的关键是对S。 肺炎杆菌最重要的毒力因子，它使用的保护性多糖(糖基)胶囊 避开我们的免疫系统。 我们的实验室现在已经确定了一组关键的蛋白质，这些蛋白质在肺炎链球菌中协同工作，并基于它们的 高度保守，可能有许多其他病原体，以使侵袭性和疾病。我们已将 调控这一过程的集体蛋白质和小分子称为胶囊调节级联，简称CRC。在……里面 在这项工作中，我们将阐明CRC如何使肺炎链球菌通过了解 这个信号网络的分子和细胞相互作用。我们实现这一目标的方法包括 在最小的水平上(原子)观察CRC，通过可视化它在整个活动物体内的作用 实时的。我们的研究结果将为这种病原体如何利用CRC提供前所未有的见解 导致疾病，为新的治疗策略铺平了道路，针对所有血清型，而不仅仅是 当前疫苗中包含的子集。最后，CRC与人类中的蛋白质有同源性 人类疾病的关键调节因素，如癌症、心肌病和癫痫。因此我们预测我们的 数据将为这些和其他人类疾病的表现机制提供宝贵的洞察力。

Project Abstract Streptococcus pneumoniae is one of the world's most debilitating human pathogens, and in the US is the most common cause of community acquired bacterial pneumoniae, despite having an available vaccine. As the vaccine can only contain some of the strains needed for immunity, we must find alternative treatments that target all 93+ different versions (or serotypes) of this deadly pathogen. One of the largest problems in pneumococcal research is understanding how this pathogen can quickly convert from a harmless nasal commensal to invasive pathogen. Key to understanding this crucial transition is the regulation of one of S. pneumoniae's most important virulence factors, the protective polysaccharide (sugar-based) capsule it uses to avoid our immune system. Our lab has now identified a crucial set of proteins that work together in S. pneumoniae, and based on their high conservation likely many other pathogens, to enable invasiveness and disease. We have named the collective proteins and small molecules that regulate this process the Capsule Regulatory Cascade, or CRC. In this work we will elucidate how the CRC enables S. pneumonaie to invade the lung by understanding the molecular and cellular interactions of this signaling network. Our methods to achieve this goal will include looking at the CRC at the smallest level (atoms), through visualization of its action within whole live animals in real time. Results from our studies will give unprecedented insight as to how this pathogen uses the CRC to cause disease, paving the way for novel therapeutic strategies targeting all serotypes rather than just the subset contained in the current vaccines. Finally, the CRC shares homology with proteins in humans that are crucial regulators of human disease, such as cancer, cardiomyopathy and epilepsy. We thus predict that our data will lend valuable insight into the mechanism by which these and other human diseases manifest.