Analysis of Mga from the Group A Streptococcus

描述（由申请人提供）：A群链球菌（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经进化出特定机制来表达适当的毒力属性。Mga是一种GAS的dna结合蛋白，它调节几个关键毒力基因的转录，这些基因编码的产物是GAS在宿主体内对生长阶段和其他环境条件的定殖和免疫逃避所必需的。此外，在许多其他致病性链球菌中也发现了参与毒力基因调控的Mga同源物。因此，Mga为研究GAS发病机制的全球调控网络提供了一个很好的系统，也为革兰氏阳性病原体的毒力调控新家族提供了一个范例。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，以更好地了解这一关键的GAS毒力调节因子对链球菌疾病的作用机制，以及(b)提高我们对这些和其他重要病原体中相互作用以广泛控制毒力的全球调控途径的总体理解。这个项目的具体目标是(1)的预测功能域内首先参与信号转导和Mga-dependent转录调控(2)检查Mga-dependent自动激活的机制和公司——独立监管公司发起人(Pmga)(3)建立地置大概和潜在作用AmrA地区其他上游的因素在增长阶段控制公司和公司的调节子和(4)调查如何增长阶段公司的监管在小鼠GAS感染期间，调节因子对毒力有贡献。对Mga及其调控机制的深入了解，不仅对gga，而且对其他革兰氏阳性病原体的全球毒力调控机制也有重要的新见解。

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.