Contribution of LiaFSR to pathogenesis and carriage of group A Streptococcus

LiaFSR 对 A 族链球菌发病机制和携带的贡献

• 批准号: 10082424
• 负责人: Anthony Richard Flores
• 金额: $ 38.5万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-16 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10082424
• 关键词: Adherence; Affect; Amino Acids; Antibiotics; Arginine; Bacteria; Benign; Biological Assay; Carrier State; Cell Wall; ChIP-seq; Detection; Diagnostic; Disease; Eating; Event; Firefly Luciferases; Foundations; Future; Gene Expression Regulation; Gene Targeting; Genes; Genetic Determinism; Glean; Glycine; Goals; Gram-Positive Bacteria; Growth; High-Throughput Nucleotide Sequencing; Human; In Vitro; Infection; Investigation; Lead; Learning; Light; Molecular Genetics; Morbidity - disease rate; Mucous Membrane; Mutation; Necrotizing fasciitis; Pathogenesis; Pharyngeal structure; Pharyngitis; Phenotype; Phosphoric Monoester Hydrolases; Phosphorylation; Phosphotransferases; Plasma; Positioning Attribute; Regulator Genes; Regulon; Reporter; Research; Saliva; Serotyping; Signal Transduction; Streptococcus pyogenes; Surface; Symptoms; System; Testing; Time; Virulence; antimicrobial peptide; base; chromatin immunoprecipitation; human pathogen; in vivo Model; mortality; mutant; mutation carrier; pathogenic bacteria; response; sensor; therapeutic development; transcriptome; transcriptome sequencing; vaccine development

Contribution of LiaFSR to pathogenesis and carriage of group A Streptococcus PROJECT SUMMARY Asymptomatic carriage of bacterial pathogens is a common but poorly understood phenomenon. Group A Streptococcus (GAS) is the cause of severe infections such as the “flesh-eating” necrotizing fasciitis and more benign infections like pharyngitis. However, GAS is also carried in the throats of humans in the absence of symptoms (i.e. asymptomatic carriage). We understand little of the bacterial molecular genetic determinants contributing to GAS carriage. We hypothesize that mutations in GAS carrier strains contribute to a unique phenotype characterized by increased ability to adhere to mucosal surfaces and decreased ability to cause disease. We identified a mutation, unique to a GAS carrier strain, leading to a single amino acid change in a highly conserved sensor kinase, LiaS, of the poorly described GAS regulatory three component system (3CS) LiaFSR. We previously showed complete recapitulation of the carrier phenotype (increased adherence to mucosal surfaces and decreased virulence) when the carrier mutation in liaS was introduced into a serotype- matched disease-causing strain of GAS. We also discovered that the carrier mutation altered global gene regulation. The LiaFSR 3CS has been described in other bacteria but its contribution to virulence gene regulation in pathogenic bacteria is largely unknown. Further, the mechanism by which the carrier amino acid change in LiaS leads to gene dysregulation and the carrier phenotype is incomplete. We hypothesize that the carrier mutation alters function of the sensor kinase, LiaS, resulting in decreased activation of the target response regulator, LiaR, affecting gene regulation and leading to the carrier phenotype. By defining the mechanism by which the carrier mutation alters gene regulation and leads to a carrier phenotype, we may better understand the gene regulatory events associated with the transition from disease to carriage in GAS. We have proposed three aims to test our hypothesis. In Aim 1, we will define in vitro and ex vivo-human conditions that activate the LiaFSR system. Aim 2 will determine global gene regulation by LiaFSR in GAS and define the genes affected by the carrier LiaS mutation. In Aim 3, we will demonstrate the effect of the carrier mutation on the function of LiaS and subsequent response regulator activation. Upon completion of these aims, we will have defined the mechanism by which the carrier mutation leads to gene dysregulation and the carrier phenotype and simultaneously learned more about gene regulation in GAS pathogenesis. Ultimately, these studies will provide a foundation for future carriage research and potentially have implications in diagnostic, therapeutic, and vaccine development for GAS and other bacterial pathogens.

LiaFSR在A组链球菌致病和携带中的作用 项目摘要 细菌病原体的无症状携带是一种常见但知之甚少的现象。A组 链球菌（GAS）是严重感染的原因，如“食肉”坏死性筋膜炎等 良性感染如咽炎。然而，GAS也在缺乏的情况下被携带在人类的喉咙中。 症状（即无症状携带）。我们对细菌的分子遗传决定因素知之甚少 为GAS运输做出贡献。我们假设GAS携带者菌株的突变导致了一种独特的 以粘附于粘膜表面的能力增加和引起粘附的能力降低为特征的表型 疾病我们发现了一种GAS携带者菌株特有的突变，导致了GAS基因中单个氨基酸的改变。 高度保守的传感器激酶，LiaS，缺乏描述的GAS调节三组分系统（3CS） LiaFSR.我们以前显示了携带者表型的完全重现（增加了对 粘膜表面和降低的毒力）时，在liaS中的载体突变被引入到血清型- 匹配的GAS致病菌株我们还发现携带者突变改变了全局基因 调控LiaFSR 3CS已在其他细菌中描述，但其对毒力基因的贡献 致病菌的调节在很大程度上是未知的。此外，载体氨基酸 LiaS的改变导致基因失调，携带者表型不完整。我们假设 携带者突变改变了传感器激酶LiaS的功能，导致靶点的激活降低 反应调节因子LiaR，影响基因调控并导致携带者表型。通过定义 携带者突变改变基因调控并导致携带者表型的机制，我们可以 更好地了解与GAS从疾病到携带的转变相关的基因调控事件。 我们提出了三个目标来检验我们的假设。在目标1中，我们将定义体外和离体人 激活LiaFSR系统的条件。目的2将确定在GAS中通过LiaFSR进行的全局基因调控 并确定受携带者LiaS突变影响的基因。在目标3中，我们将展示 携带者突变对LiaS功能的影响以及随后的应答调节因子激活。完成后 为了达到这些目标，我们将确定携带者突变导致基因失调的机制， 携带者表型，同时了解更多关于GAS发病机制的基因调控。 最终，这些研究将为未来的运输研究提供基础，并可能产生影响 用于GAS和其他细菌病原体的诊断、治疗和疫苗开发。

项目成果

ExPortal and the LiaFSR Regulatory System Coordinate the Response to Cell Membrane Stress in Streptococcus pyogenes.

ExPortal 和 LiaFSR 监管系统协调化脓性链球菌对细胞膜应激的反应。

• DOI: 10.1128/mbio.01804-20
• 发表时间: 2020
• 期刊: mBio
• 影响因子: 6.4
• 作者: Lin,Yibin;Sanson,MisuA;Vega,LuisAlberto;Shah,Brittany;Regmi,Shrijana;Cubria,MBelen;Flores,AnthonyR
• 通讯作者: Flores,AnthonyR