Analysis of Mga from the Group A Streptococcus

描述（由申请方提供）：A组链球菌（化脓性链球菌，GAS）是一种具有重要医学意义的细菌病原体，在遇到特定宿主组织时，已进化出特定机制以表达一组适当的毒力属性。Mga是GAS的DNA结合蛋白，其调节几种关键毒力基因的转录，所述基因编码响应于生长阶段和其他环境条件的GAS在宿主中的定殖和免疫逃避所必需的产物。此外，在许多其他致病性链球菌中发现了参与毒力基因调控的Mga的直系同源物。因此，Mga提供了一个很好的系统，研究全球监管网络参与GAS发病机制，以及一个新的家庭的革兰氏阳性病原体的毒力调节剂的范例。本次更新申请的总体目标是（a）继续对Mga及其启动子进行结构/功能分析，以更好地了解这种关键GAS毒力调节因子导致链球菌疾病的机制，以及（B）提高我们对相互作用以广泛控制这些和其他重要病原体毒力的全球调控途径的总体理解。本项目的具体目的是（1）表征Mga内预测的功能结构域在信号转导和Mga依赖性转录调节中的作用（2）研究Mga启动子（Pmga）处的Mga依赖性自激活和Mga非依赖性调节的机制（3）确定AmrA和潜在的其他上游因子在mga和Mga调节子的生长期控制中的作用，以及（4）研究生长期调节Mga调节子如何影响GAS感染小鼠的毒力。对Mga及其调控的深入了解将有助于不仅在GAS中，而且在其他革兰氏阳性病原体中对全球毒力调控的有价值的新见解。

DESCRIPTION (provided by applicant): The group A streptococcus (Streptococcus pyogenes, GAS) is a bacterial pathogen of significant medical importance that has evolved specific mechanisms to express an appropriate set of virulence attributes upon encountering a particular host tissue. Mga is a DNA-binding protein of GAS that regulates the transcription of several key virulence genes encoding products essential for colonization and immune evasion of GAS in the host in response to the growth phase and other environmental conditions. Furthermore, orthologues of Mga involved in virulence gene regulation are being found in many other pathogenic streptococci. Thus, Mga provides an excellent system to study global regulatory networks involved in GAS pathogenesis as well as a paradigm for a new family of virulence regulators in Gram-positive pathogens. The overall objectives of this renewal application are (a) to continue a structure/function analysis of Mga and its promoter to better understand the mechanisms by which this key GAS virulence regulator contributes to streptococcal disease, and (b) improve our general understanding of global regulatory pathways that interact to broadly control virulence in these and other important pathogens. The specific aims of this project are (1) To characterize the predicted functional domains within Mga for their role in signal transduction and Mga-dependent transcriptional regulation (2) To examine the mechanisms of Mga-dependent auto-activation and Mga- independent regulation at the mga promoter (Pmga) (3) To establish the role for AmrA and potentially other upstream factors in the growth phase control of mga and the Mga regulon and (4) To investigate how growth phase regulation of the Mga regulon contributes to virulence during GAS infection in mice. A thorough understanding of Mga and its regulation described here will contribute valuable new insights into global virulence regulation not only in GAS, but in other Gram-positive pathogens as well.