A群鏈球菌可導致人類大範圍的感染，包含了皮膚、喉嚨、血液和肌肉。其中侵襲性A群鏈球菌所造成最為嚴重的疾病為壞死性筋膜炎，被視為快速的肌肉損壞。肌肉細胞富含粒線體以提供能量來維持肌肉的正常功能。粒線體恆定性對於調控其本身的功能以及透過Parkin/PINK1路徑的粒線體自噬清除損壞的粒線體為必要的。粒線體在先天性免疫上扮演著重要的角色，病原體可藉由攻擊粒線體以保護自身在細胞內的存活。因此我們假設在A群鏈球菌是透過破壞粒線體以增加其本身在細胞內的存活進而造成肌肉損壞。首先，我們以A群鏈球菌感染老鼠的肌肉細胞，發現A群鏈球菌會導致粒線體的數量損失以及膜的破損，因此增加粒線體自噬的發生。抑制粒線體自噬可維持粒線體數量與減少胞內細菌數量，顯示抑制粒線體自噬作用有助於胞內細菌的清除。為了評估細菌毒力因子對粒線體的影響，我們篩選毒力基因突變鏈球菌，發現其中鏈球菌溶血素S (SLS)突變株只會引起輕微的粒線體數量損失和粒線體自噬。由於SLS是一個會造成穿孔的毒素，我們更發現SLS突變株導致較輕微的粒線體膜的破損、細胞色素c的釋出、OPA1的降解及粒線體斷裂，顯示SLS與CCCP的作用相似。另外，前處理CCCP後再感染SLS突變株可以增加胞內細菌的存活。除此之外，從小鼠實驗中，我們發現SLS會導致嚴重的肌肉損壞與粒線體型態的變化。總結我的研究結果，我們證實了A群鏈球菌的感染會透過SLS引發粒線體的破壞所造成的粒線體自噬，進一步增加胞內細菌存活，顯示粒線體在A群鏈球菌的感染中扮演了不可或缺的保護角色。

Group A streptococcus (GAS) causes a wide range of infections on human, including skin, throat, blood, and muscles. The most severe form of invasive group A streptococcal disease is necrotizing fasciitis described as rapidly muscular destruction. Muscles are responsible for energetic functions provided by abundant mitochondria. Mitochondria homeostasis is essential for the regulation of its function and the dysfunctional mitochondria can be eliminated through Parkin/PINK1-dependent mitophagy. Mitochondria play an important role in innate immunity that pathogens target to mitochondria as a strategy for preserving intracellular survival. Thus, we hypothesized that GAS induced muscular destruction that increases the intracellular bacterial survival is through damaging mitochondria. First, we infected mouse myoblasts, C2C12, with GAS and found that GAS caused loss of mitochondrial contents and permeabilized mitochondrial membrane thus increased mitophagy. Attenuation of mitophagy preserved mitochondrial contents and decreased intracellular bacterial number, suggesting inhibiting mitophagy was beneficial for intracellular bacterial clearance. To assess which bacterial virulence factor contributed to the disturbance of mitochondria, we found that streptolysin S (SLS) mutant induced less mitochondrial loss and mitophagy. Due to SLS is a pore-forming toxin, we found that SLS mutant caused less mitochondrial permeabilization, cytochrome c release, OPA1 degradation and mitochondrial fission, suggesting the effect of SLS was similar to that of the protonophore CCCP. In addition, CCCP pre-treatment and infection with SLS mutant could enhance intracellular bacterial survival. Furthermore, we found that GAS with SLS led to severe muscular damage and the alteration of mitochondrial morphology in vivo. Taken together, we found that GAS infection triggered mitophagy mediated by mitochondrial damage which contributed by SLS and further promoted intracellular bacterial survival, suggesting mitochondria played a critical innate protective role during GAS infection.

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