A Regulatory Cascade that Controls Pneumococcal Capsule Biosynthesis

项目摘要 肺炎链球菌是世界上最致命的人类病原体之一，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。为 疫苗只能包含免疫所需的一些菌株，我们必须找到替代治疗方法， 针对这种致命病原体的所有93种以上不同版本（或血清型）。最大的问题之一， 肺炎球菌的研究正在了解这种病原体是如何从无害的鼻腔病毒迅速转化为 入侵性病原体。理解这一关键转变的关键是S. 肺炎的最重要的毒力因子，保护性多糖（糖基）胶囊，它用来 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，它们在S。肺炎，并根据他们的 高保守性可能使许多其他病原体，使入侵和疾病。我们将其命名为 这些蛋白质和小分子共同调节这个过程，称为“胶囊调节级联”（Capsule Regulatory Cascade，CRC）。在 在这项工作中，我们将阐明CRC如何使S。肺炎侵入肺部，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将包括 在最小的水平（原子）上观察CRC，通过可视化其在整个活体动物中的作用， 真实的时间。我们的研究结果将提供前所未有的洞察力，以了解这种病原体如何利用CRC， 导致疾病，为针对所有血清型而不仅仅是 目前疫苗中的疫苗。最后，CRC与人类中的蛋白质具有同源性， 人类疾病的关键调节因子，如癌症、心肌病和癫痫。因此，我们预测， 这些数据将有助于深入了解这些疾病和其他人类疾病的发病机制。

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.