IL-1 regulation of group A Streptococcus infection

摘要炎性体的关键炎症产物，促炎细胞因子白细胞介素-1 β (IL-1β），是感染最早和最重要的警报之一。候选人的初步数据，博士。 Christopher LaRock展示了用于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）严重感染的报告显著增加有关。 通过坏死性筋膜炎等侵入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、GAS是十大感染相关病因之一 死亡率在世界上。然而，像咽炎这样相对轻微的感染也使GAS成为世界上最严重的疾病之一。 常见病原体最终，GAS侵入组织并导致最严重疾病的能力是 受IL-1β的限制;用治疗性抗炎药去除这一屏障，从而增加了 GAS感染比任何其他病原体都要多。同时揭示了一个严重的不利影响， 如果不及早发现，预后不良，这一观察结果也为分子生物学提供了基本的见解。 GAS的发病机制也就是说，IL-1β的过度活化独立于炎性小体发生。 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， 能产生信号的形式，建立高度炎症状态。因此，这些发现代表了 这是一个范例，其中IL-1β和炎性小体在免疫中不一定具有重叠的功能。的 K22提案中定义的研究方向检查了SpeB对IL-1β的生化激活， 结果的信号传导活性，以及这种炎症如何控制侵袭性皮肤小鼠模型中的GAS 感染和咽炎。了解所涉及的分子机制可以深入了解 GAS的发病机制，可以导致新的治疗策略，并深入了解发生的炎症 在其他几种主要细菌病原体的感染期间。实现这一目标需要多管齐下 方法，受益于LaRock博士对炎性小体的研究生研究，并在 他量身定制的博士后培训，整合了感染的动物模型，革兰氏阳性细菌学， 病原体和蛋白酶生物化学。这个K22奖提供了追求这部小说的手段，重要的是 研究方向，并产生初步的数据，以支持未来的初级教师和R 01赠款申请 研究GAS发病机制的分子机制，更广泛地说， 其它疾病

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.