Analysis of Mga from the Group A Streptococcus

描述(由申请人提供)：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，它进化出特定的机制，在遇到特定宿主组织时表达一组适当的毒力属性。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在寄主中定植和免疫逃避所必需的，以响应生长阶段和其他环境条件。此外，参与毒力基因调控的MGA的同源基因在许多其他致病链球菌中也被发现。因此，MGA为研究涉及GAS发病机制的全球调控网络提供了一个很好的系统，并为革兰氏阳性病原体的新的毒力调节家族提供了一个范例。此次更新申请的总体目标是(A)继续对MGA及其启动子的结构/功能进行分析，以更好地了解这种关键的气体毒力调节因子导致链球菌疾病的机制，以及(B)提高我们对全球调控途径的总体理解，这些调控途径相互作用，广泛控制这些和其他重要病原体的毒力。本项目的具体目标是(1)确定MGA内预测的功能结构域在信号转导和MGA依赖转录调控中的作用；(2)检测MGA启动子(Pmga)依赖于MGA的自激活和MGA非依赖调控的机制；(3)确定Amra和其他潜在的上游因子在生长阶段控制MGA和MGA调节子中的作用；(4)研究MGA调节子的生长期调节如何在GAS感染小鼠的毒力中贡献作用。对MGA及其调控的透彻理解将有助于对全球毒力调控的有价值的新见解，不仅在GAS中，而且在其他革兰氏阳性病原体中也是如此。

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.