壞死性筋膜炎是侵襲性A型鏈球菌所造成最嚴重的疾病型態，病理現象主要是呈現肌肉快速損壞伴隨凝血機制紊亂與血管功能障礙。宿主遭遇侵襲性A型鏈球菌感染高度誘發前發炎性細胞激素 (IL-1進一步引起血管內皮功能障礙、瀰漫性血管內凝血、微血管洩漏以及多器官功能衰竭。IL-1已知是由炎症小體inflammasome調控活化之caspase-1活化切割。然而，促成壞死性筋膜炎病理機制非常複雜，許多基本問題仍然所知甚少。在這裡，我們成功以肌肉注射的動物模式重現壞死性筋膜炎，不但產生肌肉壞死和血管功能紊亂，也誘發炎症小體活化並伴隨大量前發炎性細胞激素 (IL-1釋放。另外，在細胞實驗當中，血管內皮細胞也可在Ａ型鏈球菌感染之後活化炎症小體。進一步抑制caspase-1活性，內皮細胞釋放出pyroptosis標記物質LDH和HMGB-1皆明顯減少，細胞外的細菌數也同時降低；在活體中，caspase-1有效防止A型鏈球菌誘導的肌肉炎症小體激活和肌肉損傷。進一步，我們證明A型鏈球菌的毒力因子，鏈球菌溶血素S (SLS)，參與在內皮細胞炎症小體活化及pyropotosis的過程。在活體試驗中，SLS突變株較無法誘發肌肉炎症小體活化和嚴重的肌肉破壞。整體而言，我們推測：內皮細胞炎症小體活化可能產生過度發炎反應，進而加重侵襲性A型鏈球菌所造成的急性肌肉壞死。綜上所述，我們證明了透過鏈球菌溶血素S逃脫吞噬體的A型鏈球菌，誘發內皮細胞炎症小體活化及典型的caspase-1依賴型的pyroptosis，使得細菌逃脫出細胞外，進而引起嚴重的肌肉破壞。因此，我們推測A型鏈球菌誘導快速肌肉破壞是內皮細胞炎症小體活化而造成過度發炎反應的結果。

The most severe form of invasive GAS disease is necrotizing fasciitis described as rapidly muscle destruction with marked coagulation disturbance and vascular dysfunction. In response to invasive GAS disease, a large quantity of proinflammatory cytokine, IL-1, is induced and associated with vascular dysfunction, disseminated intravascular coagulation (DIC), microvascular leakage and multiple organ dysfunctions. IL-1β is known to be processed by caspase-1, a cysteine protease regulated by a multiprotein complex called inflammasome. However, the pathogenesis in necrotizing fasciitis is so complicated that many fundamental questions remain poorly understood. Here, we successfully reconstructed the animal model of necrotizing fasciitis that myonecrosis and vascular damages were induced by intramuscular injection of GAS, and inflammasome activation accompanied with large amount of IL-1β production were found. In addition, endothelial inflammasome activations were induced by GAS infection. Pyroptosis markers, released LDH and HMGB-1, and extracellular bacterial numbers were prohibited by caspase-1 inhibitor in GAS-infected endothelial cells. Blockage of caspase-1 in vivo prevented GAS-induced muscular inflammasome activation and muscular damage. Further, we demonstrated that streptolysin S of GAS involved in GAS-induced endothelial inflammasome activation and pyropotosis by infection with isogenic SLS mutant. In addition, the SLS mutant lost its capacity causing muscular inflammasome activation and severe muscle destruction in vivo. Taken together, we demonstrated that phagosomal escaped GAS, which mediated by SLS, induced severe muscle destruction was mediated through endothelial inflammasome activation accompanied with a canonical caspase-1 dependent pyroptosis and further released the cytosomal GAS. Thus, we hypothesized that rapid muscle destruction induced by GAS is the consequence of excessive inflammatory responses followed by endothelial inflammasome activation.

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