化膿性鏈球菌(Streptococcus pyogenes)又稱作A群鏈球菌(group A streptococcus，簡稱GAS)為感染人類之致病菌,造成輕微的表皮感染到嚴重深層組織的侵入性疾病。PerR (peroxide stress response regulator) 為GAS之調控因子，已知和GAS適應氧化壓力反應及鐵的平衡有關，而perR突變株對於抵抗多形核白血球的清除能力比野生株低。利用二維電泳分析，發現perR突變株與野生株有19個分泌型蛋白質表現具有顯著的差異。其中一蛋白質為mitogenic factor 3 (Mf3)，為已知的DNase。本研究主要探討PerR對於Mf3及其他DNase的調控以及此調控在GAS致病機轉中的角色。為了瞭解mf3的毒力,我們進一步構築mf3的突變株,發現其在人類全血中的存活能力較低，且在小鼠感染中的毒力也會下降。mf3的表現和生長曲線呈正相關，但perR突變株mf3的表現量會多於野生株。進一步分析PerR對GAS三個DNase基因(sda1，spd及mf3)的調控。在一般培養液培養下，sda1的表現量在perR突變株及野生株並沒有差異，但spd在培養8小時時，perR突變株的表現量增加。在硫酸亞鐵的刺激下，PerR並不會對三個DNase基因的表現造成影響。但在過氧化氫的刺激下，野生株的sda1會被誘發，且隨劑量的增加而有遞增的表現，而perR突變株中表現量卻降低。反之，在過氧化氫的刺激下，mf3及spd在野生株中則會隨著劑量增加而表現下降。此結果顯示在氧化壓力下PerR 為sda1表現必需的調控因子。在已知的三個DNase基因中，sda1具有較強DNA 分解能力以及和GAS致病力最為相關。Sda1已被報導可分解neutrophil extracellular traps (NETs)上的DNA以逃脫免疫攻擊。將GAS和多核型白血球培養後，發現野生株感染後NETs的數目比突變株少，推測為在氧化壓力下，野生株sda1被誘發表現而增加分解NETs的能力。這些結果指出PerR為一個雙功能性的調控因子，在不同環境刺激下影響DNase基因的表現進而影響其功能，這在GAS的致病機轉中扮演一個重要的角色。

Streptococcus pyogenes (group Astreptococcus, GAS) is a bacterial pathogen restricted to human, and causes diseases ranging from superficial to deep tissue infection. In order to defend oxidative stress produced from immune cells, the regulator PerR (peroxide stress response regulator)is known to playa role in the adaptive response. PerR is also involved in regulation of iron hemostasis and is necessary for virulence of GAS. Our results showed that the perR mutant decreased resistance to PMN killing. In addition, 2-D electrophoresis analysis showed19 spots were either up regulated or down regulated expression in the perR mutant. Among them, a DNase (mitogenic factor 3, MF3) was identified and mutant was also constructed.The aimsof my project were to understand the roles of PerR in regulation of Mf3 and other DNases of GAS, and the effects of this regulation network to GAS pathogenesis. The mf3 mutant showed the decrease survival rate than the wild-typein human whole blood bactericidal assayand the attenuated virulence in mice infection. RT-PCR and real-time PCR showed increased mf3 expression in theperR mutant. Electrophoretic mobility shift assays showed PerR directly binds to Per boxes in the mf3 promoter region. In order to understand how PerR regulated DNase activity, three DNases genes (sda1,spd, and mf3) were further analyzed in wild-type and perR mutant strains under different conditions including ferrous ion and hydrogen peroxide treatment. The results showed no effect on sda1,spd, and mf3 expressionin wild-type strain under the ferrous ion treatments, while spd and mf3 expression were increased in the mutant. sda1expression was increased in wild-type strain, while mf3 and spd expressionswere decreased after hydrogen peroxide treatments.These results indicated that sda1 expression under oxidative stress is PerR-dependent. Sda1 has been found it degraded DNA of neutrophil extracellular traps (NETs) and allowed GAS to escape from phagocytes killing. In fluorescence images of NETs, less NETs were presented in wild-type thanperR mutant supporting that sda1 was only induced in wild-type strain to degrade the NET structure. In conclusion, PerR acts as a bifunctional regulator to regulate DNase gene in different environmental conditions which may play an important role in the GAS pathogenesis.

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