Interaction between LL-37 and CsrRS of group A Streptococcus

LL-37 与 A 族链球菌 CsrRS 之间的相互作用

• 批准号: 8004306
• 负责人: John Frank Love
• 金额: $ 5.58万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8004306
• 关键词: Antibiotic Therapy; Area; Binding; Flesh-Eating Bacteria; Genetic Transcription; Human; Immune system; Infection; Invaded; Life; Membrane; Microbe; Necrotizing fasciitis; Organism; Pathogenesis; Pharyngeal structure; Pharyngitis; Phenotype; Phosphotransferases; Plague; Play; Process; Public Health; Reaction; Rheumatic Heart Disease; Role; Staging; Streptococcus pyogenes; Toxic Shock Syndrome; Virulence Factors; Virulent; Work; antimicrobial peptide LL-37; cathelicidin; cell type; fascinate; improved; insight; keratinocyte; killings; macrophage; pathogen; public health relevance; response; sensor

DESCRIPTION (provided by applicant): Group A Streptococcus (GAS, also known as Streptococcus pyogenes) is a common human pathogen, most frequently causing pharyngitis or "strep throat." However, severe invasive infections like necrotizing fasciitis and toxic shock syndrome are also caused by this organism, leading to its nickname in the lay press - "flesh-eating bacteria." This work will help explain the process by which a microbe in the throat can invade and cause life-threatening illness. Previous studies found that GAS alter transcription of multiple virulence factors in response to the human cathelicidin, LL-37, an antimicrobial peptide. A membrane-bound sensor kinase (CsrS) and its cytoplasmic response regulator (CsrR) appear to drive this reaction. This application aims to examine the role of LL-37 in stimulating an invasive phenotype in GAS. We will focus on the interaction of GAS with two host cell types commonly encountered early in infection: keratinocytes and macrophages. We will examine the role that LL-37 and CsrRS play in GAS's ability to avoid internalization and killing. Overall, these studies will examine a fascinating evolutionary interaction between a human pathogen and the innate immune system, offering new insights into the pathogenesis of GAS infections. PUBLIC HEALTH RELEVANCE: The public health burden of GAS infection remains high. Sequelae of infection, including rheumatic heart disease, continue to plague especially developing areas, where prompt antibiotic therapy is unavailable. Additionally, there has been a rise in invasive GAS infections as a new, more virulent strain has spread around the globe. For these reasons, improving our understanding of the earliest stages of human infection will be essential to battling this common yet evolving pathogen.

描述（由申请人提供）：A 组链球菌（GAS，也称为化脓性链球菌）是一种常见的人类病原体，最常引起咽炎或“链球菌性咽喉炎”。然而，坏死性筋膜炎和中毒性休克综合症等严重侵袭性感染也是由这种微生物引起的，因此它在外行媒体中被称为“食肉细菌”。这项工作将有助于解释喉咙中的微生物侵入并导致危及生命的疾病的过程。先前的研究发现，GAS 会改变多种毒力因子的转录，以响应人类抗菌肽 LL-37。膜结合传感器激酶 (CsrS) 及其细胞质反应调节器 (CsrR) 似乎驱动该反应。本申请旨在研究 LL-37 在刺激 GAS 侵袭表型中的作用。我们将重点关注 GAS 与感染早期常见的两种宿主细胞类型的相互作用：角质形成细胞和巨噬细胞。我们将研究 LL-37 和 CsrRS 在 GAS 避免内化和杀伤的能力中所发挥的作用。总的来说，这些研究将研究人类病原体和先天免疫系统之间令人着迷的进化相互作用，为 GAS 感染的发病机制提供新的见解。 公共卫生相关性：GAS 感染的公共卫生负担仍然很高。包括风湿性心脏病在内的感染后遗症继续困扰着特别是发展中地区，因为这些地区无法及时获得抗生素治疗。此外，随着一种新的、毒性更强的菌株在全球范围内传播，侵袭性 GAS 感染也有所增加。由于这些原因，提高我们对人类感染最早阶段的了解对于对抗这种常见但不断演变的病原体至关重要。