Central role of a bacterial two-component gene regulatory system of previously unknown function in pathogen persistence in human saliva.
Central role of a bacterial two-component gene regulatory system of previously unknown function in pathogen persistence in human saliva.
复制标题
DOI：
10.1073/pnas.0505839102
复制
发表时间：
2005-11
影响因子：
11.1
通讯作者：
S. Shelburne;P. Sumby;I. Sitkiewicz;C. Granville;F. DeLeo;J. Musser
中科院分区：
文献类型：
--
作者：
S. Shelburne;P. Sumby;I. Sitkiewicz;C. Granville;F. DeLeo;J. Musser
人们对细菌在人体内持续存在的分子遗传机制知之甚少。A组链球菌（GAS）引起人类大多数细菌性咽炎病例，并且易于持续存在于上呼吸道。为了获得有关GAS如何在口咽中存活并感染口咽的信息，我们分析了在唾液中生长的血清型M1菌株的转录组。编码未知功能的双组分基因调控系统的基因[spy 0874/0875，本文称为sptR和sptS（sptR/S），用于唾液持久性]转录物变化的动态模式表明SptR/S有助于唾液中GAS的持久性。与这一想法相一致，一个同基因的非极性突变株（DeltasptR）是显着减少能够在唾液中生存的亲本菌株相比。在唾液中生长的细菌的迭代表达微阵列分析显示，在DeltasptR突变株中，几个已知的和推定的GAS毒力因子基因的转录物显著降低。与亲本菌株相比，同基因突变菌株还具有参与复杂碳水化合物获取和利用途径的多个编码蛋白质的基因的转录物的改变。从患有咽炎的人的咽拭子中提取的GAS的Western免疫印迹分析和实时PCR分析证实了这一发现。我们的结论是，SptR/S优化了GAS在人唾液中的持久性，显然是通过战略性地影响代谢途径和毒力因子的产生。发现一种遗传程序，显着增加唾液中主要人类病原体的持久性，增强了对细菌如何在宿主中生存的理解，并提出了新的治疗策略。
The molecular genetic mechanisms used by bacteria to persist in humans are poorly understood. Group A Streptococcus (GAS) causes the majority of bacterial pharyngitis cases in humans and is prone to persistently inhabit the upper respiratory tract. To gain information about how GAS survives in and infects the oropharynx, we analyzed the transcriptome of a serotype M1 strain grown in saliva. The dynamic pattern of changes in transcripts of genes [spy0874/0875, herein named sptR and sptS (sptR/S), for saliva persistence] encoding a two-component gene regulatory system of unknown function suggested that SptR/S contributed to persistence of GAS in saliva. Consistent with this idea, an isogenic nonpolar mutant strain (DeltasptR) was dramatically less able to survive in saliva compared with the parental strain. Iterative expression microarray analysis of bacteria grown in saliva revealed that transcripts of several known and putative GAS virulence factor genes were decreased significantly in the DeltasptR mutant strain. Compared with the parental strain, the isogenic mutant strain also had altered transcripts of multiple genes encoding proteins involved in complex carbohydrate acquisition and utilization pathways. Western immunoblot analysis and real-time PCR analysis of GAS in throat swabs taken from humans with pharyngitis confirmed the findings. We conclude that SptR/S optimizes persistence of GAS in human saliva, apparently by strategically influencing metabolic pathways and virulence factor production. The discovery of a genetic program that significantly increased persistence of a major human pathogen in saliva enhances understanding of how bacteria survive in the host and suggests new therapeutic strategies.