Université Paris Cité, Institut Cochin, INSERM, U1016, CNRS, UMR8104, Paris, France.
Service de Bactériologie, CNR des Streptocoques, Hôpitaux Universitaires Paris Centre, Paris, France.
J Bacteriol. 2023 Apr 25;205(4):e0003923. doi: 10.1128/jb.00039-23. Epub 2023 Mar 15.
Streptococcus pyogenes, also known as group A Streptococcus, causes a wide variety of diseases ranging from mild noninvasive to severe invasive infections. To identify possible causes of colonization-to-invasive switches, we determined the genomic sequences of 10 isolates from five pairs each composed of an invasive strain and a carriage strain originating from five infectious clusters. Among them, one pair displayed a single-nucleotide difference in , encoding the sensor histidine kinase of the two-component CovRS system that controls the expression of 15% of the genome. In contrast to previously described cases where the invasive strains harbor nonfunctional CovS proteins, the carriage strain possessed the mutation , leading to the replacement of the tyrosine at position 39 by a histidine. The CovSY39H mutation affected the expression of the genes from the CovR regulon in a unique fashion. Genes usually overexpressed in mutant strains were underexpressed and vice versa. Furthermore, the mutant strain barely responded to the addition of the CovS-signaling compounds Mg and LL-37. The variations in the accumulation of two virulence factors paralleled the transcription modifications. In addition, the mutant strain showed less survival than its wild-type counterpart in murine macrophages. Finally, in two murine models of infection, the mutant strain was less virulent than the wild-type strain. Our study suggests that the CovSY39H protein compromises CovS phosphatase activity and that this yields a noninvasive strain. Streptococcus pyogenes, also known as group A Streptococcus, causes a wide variety of diseases, leading to 517,000 deaths yearly. The two-component CovRS system, which responds to MgCl and the antimicrobial peptide LL-37, controls the expression of 15% of the genome. Invasive strains may harbor nonfunctional CovS sensor proteins that lead to the derepression of most virulence genes. We isolated a colonization strain that harbors a novel mutation. This mutant strain harbored a transcriptome profile opposite that of other mutant strains, barely responded to environmental signals, and was less virulent than the wild-type strain. This supports the importance of the derepression of the expression of most virulence genes, via mutations that impact the phosphorylation of the regulator CovR, for favoring S. pyogenes invasive infections.
化脓链球菌，也被称为 A 组链球菌，可引起多种疾病，从轻微的非侵袭性到严重的侵袭性感染不等。为了确定定植-侵袭性转变的可能原因，我们从五个感染群中每组各五个侵袭株和携带株中确定了 10 株的基因组序列。其中，一对菌株在编码双组分 CovRS 系统传感器组氨酸激酶的 中存在单个核苷酸差异，该系统控制基因组的 15%表达。与先前描述的侵袭株携带无功能 CovS 蛋白的情况不同，携带株携带突变 ，导致位置 39 的酪氨酸被组氨酸取代。CovSY39H 突变以独特的方式影响 CovR 调控子基因的表达。通常在 突变株中过度表达的基因表达水平降低，反之亦然。此外， 突变株对 CovS 信号化合物 Mg 和 LL-37 的添加几乎没有反应。两种毒力因子的积累变化与转录修饰平行。此外，与野生型相比， 突变株在鼠巨噬细胞中的存活率更低。最后，在两种感染小鼠模型中， 突变株的毒力比野生型菌株低。我们的研究表明，CovSY39H 蛋白会损害 CovS 磷酸酶的活性，从而产生非侵袭性菌株。化脓链球菌，也被称为 A 组链球菌，可引起多种疾病，每年导致 51.7 万人死亡。双组分 CovRS 系统对 MgCl 和抗菌肽 LL-37 作出反应，控制基因组的 15%表达。侵袭株可能携带无功能的 CovS 传感器蛋白，导致大多数毒力基因的去阻遏。我们分离出一株携带新型 突变的定植株。该突变株的转录组图谱与其他 突变株相反，对环境信号几乎没有反应，且比野生型菌株的毒力更低。这支持了通过影响调控因子 CovR 的磷酸化来解除大多数毒力基因表达抑制，有利于化脓链球菌侵袭性感染的重要性。
