Department of Infectious Diseases, MD Anderson Cancer Center, Houston, Texas, USA.
Mathomics, Center for Mathematical Modeling, Universidad de Chile, Beauchef 851, 7th Floor, Santiago, Chile.
Sci Rep. 2016 Sep 1;6:32442. doi: 10.1038/srep32442.
Catabolite control protein A (CcpA) is a highly conserved, master regulator of carbon source utilization in gram-positive bacteria, but the CcpA regulon remains ill-defined. In this study we aimed to clarify the CcpA regulon by determining the impact of CcpA-inactivation on the virulence and transcriptome of three distinct serotypes of the major human pathogen Group A Streptococcus (GAS). CcpA-inactivation significantly decreased GAS virulence in a broad array of animal challenge models consistent with the idea that CcpA is critical to gram-positive bacterial pathogenesis. Via comparative transcriptomics, we established that the GAS CcpA core regulon is enriched for highly conserved CcpA binding motifs (i.e. cre sites). Conversely, strain-specific differences in the CcpA transcriptome seems to consist primarily of affected secondary networks. Refinement of cre site composition via analysis of the core regulon facilitated development of a modified cre consensus that shows promise for improved prediction of CcpA targets in other medically relevant gram-positive pathogens.
代谢物控制蛋白 A (CcpA) 是一种高度保守的革兰氏阳性菌碳源利用的主要调控因子，但 CcpA 调控网络仍不明确。在这项研究中，我们旨在通过确定 CcpA 失活对三种不同血清型主要人类病原体 A 组链球菌 (GAS) 的毒力和转录组的影响来阐明 CcpA 调控网络。CcpA 失活显著降低了 GAS 在广泛的动物挑战模型中的毒力，这与 CcpA 对革兰氏阳性细菌发病机制至关重要的观点一致。通过比较转录组学，我们确定了 GAS 的 CcpA 核心调控网络富含高度保守的 CcpA 结合基序（即 cre 位点）。相反，CcpA 转录组在菌株间的差异似乎主要由受影响的二级网络组成。通过对核心调控网络进行 cre 位点组成的优化，开发了一种改良的 cre 共识，有望改善对其他与医学相关的革兰氏阳性病原体中 CcpA 靶标的预测。
