IL-1 regulation of group A Streptococcus infection

总结。炎症体的关键炎症产物--促炎细胞因子白细胞介素1β 白介素1受体(IL-1β)，是最早也是最重要的感染警报之一。候选人Dr。 克里斯托弗·拉洛克展示了治疗自身炎症性疾病的IL-1β抑制免疫疗法 与A组链球菌(GAS)严重感染报告显著增加有关。 通过坏死性筋膜炎等侵袭性感染和中毒性休克综合征等并发症， 肾小球肾炎与风湿性心脏病、气肿是感染相关的十大原因之一 世界上最大的死亡率。然而，相对轻微的感染，如咽炎，也使瓦斯成为世界上最严重的 常见的病原体。最终，气体侵入组织并导致最严重疾病的能力是 受到IL-1β的限制；用治疗性消炎药清除这一屏障，从而增加了 气体感染比其他任何病原体都严重。同时暴露出具有严重不良影响的 如果不及早发现，预后很差，这一观察也提供了对分子的基本见解 GAS的发病机制。也就是说，IL-1β的过度激活独立于炎症小体发生。 从机理上讲，这是因为链球菌蛋白酶SpeB可以直接将IL-1β加工成成熟的、 信号传递能力强的形式，建立高度炎症状态。因此，这些发现代表了一个 IL-1β和炎症体在免疫中不一定有重叠功能的范式。这个 本K22提案中确定的研究方向是检测SpeB对IL-1β的生化激活， 导致的信号活动，以及这种炎症如何控制侵袭性皮肤模型中的气体 感染和咽炎。了解其中涉及的分子机制有助于深入了解 GAS的发病机制可以导致新的治疗策略，并深入了解所发生的炎症 在被其他几种主要细菌病原体感染期间。要做到这一点，需要多管齐下 方法，受益于LaRock博士对炎症小体的研究生研究，并在 他量身定做的博士后培训，融合了感染动物模型、革兰氏阳性细菌学 病原体和蛋白酶生物化学。这个K22奖项提供了追求这部小说的手段，重要的是 研究方向和生成初步数据，以支持未来初级教员和R01拨款申请 探讨GAS发病的分子机制，以及IL-1β在GAS发病过程中的调控 其他疾病。

SUMMARY. A key inflammatory output of the inflammasome, the proinflammatory cytokine interleukin-1beta (IL-1β), is one of the earliest and most important alarms to infection. Preliminary data by the candidate, Dr. Christopher LaRock, shows IL-1β-inhibiting immunotherapies for the treatment of autoinflammatory disease are associated with significantly increased reports of severe infections by group A Streptococcus (GAS). Through invasive infections like necrotizing fasciitis and complications like toxic shock syndrome, glomeruloronephritis, and rheumatic heart disease, GAS is one of the top ten causes of infection related mortality in the world. Yet comparatively mild infections like pharyngitis also make GAS one of the world's most common pathogens. Ultimately, the ability of GAS to invade tissue and cause the most severe diseases is limited by IL-1β; removal of this barrier with therapeutic anti-inflammatories thereby increases the risk of infection by GAS more so than for any other pathogen. While revealing a serious adverse effect that has a poor prognosis if not caught early, this observation also provides fundamental insights into molecular pathogenesis of GAS. That is, hyper-activation of IL-1β occurs independently of the inflammasome. Mechanistically, this occurs because the streptococcal protease SpeB can directly process IL-1β into a mature, signaling-competent form that establishes a hyper-inflammatory state. These findings therefore represent a paradigm where IL-1β and the inflammasome do not necessarily have overlapping functions in immunity. The research directions defined in this K22 proposal examine the biochemical activation of IL-1β by SpeB, the signaling activity that results, and how this inflammation controls GAS in murine models of invasive skin infection and pharyngitis. Understanding the molecular mechanisms involved gives insight into the pathogenesis of GAS that can lead to new therapeutic strategies, and insight into the inflammation that occurs during infections by several other leading bacterial pathogens. Accomplishing this requires a multi-pronged approach, benefiting from Dr. LaRock's graduate research on the inflammasome, and further developed during his tailored postdoctoral training that integrates animal models of infection, bacteriology of Gram-positive pathogens, and protease biochemistry. This K22 award provides the means to pursue this novel, important research direction and generate the preliminary data to support future junior faculty and R01 grant applications examining the molecular mechanisms of GAS pathogenesis and more broadly, the regulation of IL-1β during other diseases.