Streptococcus pyogenes manipulates host immunity via the Rgg2/3 quorum sensing system

化脓性链球菌通过 Rgg2/3 群体感应系统操纵宿主免疫

• 批准号: 10212919
• 负责人: KATE M RAHBARI
• 金额: $ 5.1万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-16 至 2022-08-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10212919
• 关键词: Affect; Aminoglycosides; Antigens; Bacteria; Behavior; Cell Wall; Cell surface; Cells; Chemicals; Child; Communication; Cues; Cytolysins; Cytosol; Data; Disease; Enzymes; Evaluation; Exposure to; Foundations; Future; Gene Expression; Genetic Transcription; Goals; Host Defense; Human; Immune; Immune Evasion; Immune response; Immune system; Immunity; Immunohistochemistry; In Vitro; Infection; Inflammatory; Inflammatory Response Pathway; Innate Immune Response; Knockout Mice; Label; Life Style; Lymphoid Tissue; Mannose; Mass Spectrum Analysis; Measures; Mediating; Metals; Microbial Biofilms; Modeling; Modification; Mucous Membrane; Muramidase; Mus; Nose; Operon; Oropharyngeal; Ovalbumin; Pathology; Peptide Hydrolases; Phenotype; Population; Population Group; Predisposition; Process; Proteins; Proteome; Proteomics; Rag1 Mouse; Reporter; Resistance; Role; Signal Transduction; Streptococcus pyogenes; Structure of mucous membrane of nose; Surface; Surface Properties; System; T cell response; Testing; adaptive immunity; antimicrobial; combat; cytokine; experimental study; fitness; genetic approach; human pathogen; in vivo; insight; interest; macrophage; microbial; mucosal site; novel; pathogen; quorum sensing; recruit; response; transcriptome sequencing

ABSTRACT Group A Streptococcus (GAS) is an obligate human pathogen that causes 600 million infections annually, ranging from superficial to severe and invasive. Interestingly, GAS can also asymptomatically colonize up to 30% of children. Because the reservoir for this bacterium is exclusively humans, a better understanding of mechanisms promoting the asymptomatic lifestyle of GAS can help control the persistence of this ubiquitous bacterium in the population. Like many other bacterial species, GAS utilizes chemical communication, or quorum sensing (QS) systems, to genetically coordinate behaviors across a population. Our lab has characterized the Rgg2/3 QS system and has shown that it promotes phenotypes indicative of cell surface alterations, including lysozyme resistance and biofilm formation. Our preliminary experiments show that Rgg2/3 activation also alters the host response in vitro, resulting in decreased macrophage pro-inflammatory cytokine responses, and in vivo, resulting in prolonged mouse nasopharyngeal colonization. This proposal seeks to test the hypothesis that GAS utilizes Rgg2/3 QS-mediated modifications to alter interactions with the host. We will examine the implications of these modifications on the adaptive and innate immune responses to GAS, and we will determine what altered GAS surface molecules contribute to this modulation. Understanding the role of QS in manipulating immune responses will provide additional support for developing future strategies to combat infection.

摘要 A组链球菌(GAS)是一种人类特有的病原体，每年导致6亿人感染， 从表面到严重和侵入性不等。有趣的是，气体也可以无症状地定植到 30%的儿童。因为这种细菌的宿主完全是人类，所以更好地理解 促进GAS无症状生活方式的机制可以帮助控制这种无处不在的 种群中的细菌。像许多其他细菌一样，气体利用化学交流，或称仲裁。 感知(QS)系统，以遗传方式协调整个种群的行为。我们的实验室已经确定了 Rgg2/3 QS系统，并已表明它促进指示细胞表面改变的表型，包括 溶菌酶抗性与生物被膜的形成。我们的初步实验表明，Rgg2/3的激活也会改变 宿主在体外的反应，导致巨噬细胞的促炎细胞因子反应减少，而在体内， 导致小鼠鼻咽定植时间延长。这一提议试图检验气体 利用Rgg2/3 QS介导的修饰来改变与宿主的相互作用。我们将研究其影响 这些改变对GAS的适应性和先天免疫反应的影响，我们将确定哪些改变 气体表面分子促成了这种调制。理解QS在操纵免疫中的作用 应对措施将为制定未来抗击感染的战略提供额外的支持。