Interaction between LL-37 and CsrRS of group A Streptococcus

描述(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“链球菌咽喉炎”。然而，严重的侵袭性感染，如坏死性筋膜炎和中毒性休克综合征也是由这种细菌引起的，导致它在业馀媒体上有一个绰号--“食肉细菌”。这项工作将有助于解释喉咙中的微生物入侵并导致危及生命的疾病的过程。以前的研究发现，GAS会改变多种毒力因子的转录，以响应人类抗菌肽LL-37。一种膜结合的传感蛋白(CSRs)及其细胞质反应调节因子(CsrR)似乎驱动了这一反应。这项应用旨在研究LL-37在刺激GAS侵袭性表型中的作用。我们将专注于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避免内化和杀戮能力中所起的作用。总体而言，这些研究将检验人类病原体和先天免疫系统之间有趣的进化相互作用，为GAS感染的发病机制提供新的见解。 公共卫生相关性：气体感染造成的公共卫生负担仍然很高。感染的后遗症，包括风湿性心脏病，继续困扰着特别是发展中地区，那里没有及时的抗生素治疗。此外，随着一种新的、更具毒性的毒株在全球蔓延，侵入性气体感染的人数也在上升。出于这些原因，加强我们对人类感染早期阶段的了解，将是与这种常见但不断演变的病原体作斗争的关键。

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.