Sharma Abhinay, Anand Aparna, Ravins Miriam, Zhang Xiaolan, Horstmann Nicola, Shelburne Samuel A, McIver Kevin S, Hanski Emanuel
Department of Microbiology and Molecular Genetics, The Institute for Medical Research, Israel-Canada (IMRIC), Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, 9112102, Israel.
Department of Physiology, College of Basic Medical Science, Harbin Medical University, Harbin, China.
EMBO Rep. 2025 Apr 14. doi: 10.1038/s44319-025-00447-z.
Group A Streptococcus (GAS) causes various human diseases linked to virulome expression predominantly regulated by the two-component system (TCS), CovR/S. Here, we demonstrate that asparagine (Asn) presence in a minimal chemically defined medium increases virulence gene expression in a CovR-dependent fashion. It also decreases the transcription of asparagine synthetase (AsnA), the ABC transporter responsible for Asn uptake (GlnPQ), and that of the hemolysin toxins responsible for scavenging Asn from the host. Metabolomics data show that Asn availability increases intracellular ADP/ATP ratio, which enhances phosphatase activity in structurally related CovS sensors and is probably responsible for the Asn-mediated decrease in CovR phosphorylation. Mutants deficient in AsnA, GlnPQ, asparaginase, (AsnB) activities are attenuated in a mouse model of human GAS invasive soft tissue infection. The similarity between the mechanisms of Asn-mediated regulation of GAS virulence and tumor growth suggests that, as in cancer, components maintaining Asn homeostasis could be targeted for anti-GAS treatments.
A组链球菌（GAS）会引发多种人类疾病，这些疾病与主要由双组分系统（TCS）CovR/S调控的病毒组表达有关。在此，我们证明在化学成分确定的基础培养基中存在天冬酰胺（Asn）会以CovR依赖的方式增加毒力基因的表达。它还会降低天冬酰胺合成酶（AsnA）、负责摄取Asn的ABC转运蛋白（GlnPQ）以及负责从宿主中清除Asn的溶血素毒素的转录水平。代谢组学数据表明，Asn的可利用性会增加细胞内ADP/ATP比率，这会增强结构相关的CovS传感器中的磷酸酶活性，并且可能是Asn介导的CovR磷酸化减少的原因。在人类GAS侵袭性软组织感染的小鼠模型中，AsnA、GlnPQ、天冬酰胺酶（AsnB）活性缺陷的突变体的毒力减弱。Asn介导的GAS毒力调控机制与肿瘤生长机制之间的相似性表明，与癌症一样，维持Asn稳态的成分可能成为抗GAS治疗的靶点。
