A 群鏈球菌 (Group A streptococcus, GAS) 是人類致病菌，可以對宿主造成各種疾病。GAS過去被認為是細胞外致病菌，但越來越多的研究指出，GAS能夠在細胞內存活且生長。先前團隊的初步結果顯示，GAS無法在上皮細胞 (A549) 存活，但從侵襲性疾病之病人分離出的NZ131及A20卻能夠在內皮細胞 (HMEC-1) 生長，由於，GAS在細胞內生長之機轉仍然未知，因此我擬定探討GAS在內皮細胞作用的機制。首先，針對實驗室已建構好A20之毒力因子speB和調控因子luxS、rgg、fasB突變株，以及NZ131之毒力因子speB和調控因子luxS、rgg、lacD.1、srv突變株進行實驗。結果顯示，兩菌株的rgg突變株在細胞內的生長能力均下降，但rgg突變株會造成細胞死亡，導致細胞內的菌數也變少，因此我無法確認rgg在內皮細胞內生長的角色。根據O'Seaghdha及 Wessels (2013) 在角質細胞的研究，發現若鏈球菌溶血素O與Co-Toxin NAD-glycohydrolase (NADase) 共同作用，可避免autophagolysosme的成熟，而延長A群鏈球菌在細胞中存活的時間。因此，我建構了NZ131 nga突變株 (SW957) 和回補株 (SW958) 以及將NZ131完整之nga送至SF370 (SW959)。實驗結果發現SW957在HMEC-1中生長的能力比野生株及SW958差，而SF370野生株無法在細胞內存活，但SW959且能在細胞內生長。以免疫螢光染色及西方墨點法證實，NADase陽性的菌株：NZ131野生株、SW958及SW959到了感染後期會有LC-3 punctuate以及LC-3Ⅱ表現量增加。相反的，NADase陰性的菌株：SF370及SW957則沒有此現象。此外，以lysotracker標記酸化的autophagolysosome實驗，結果顯示NADase 陰性的菌株酸化的現象較為嚴重。當加入balfilomycin A1抑制lysosome的功能後， NADase 陰性的菌株可在內皮細胞中恢復生長。總結以上，nga可避免autophagolysosome酸化清除的機制，使A群鏈球菌能在內皮細胞中生長。

Group A streptococcus (GAS) is an important human pathogen that causes diverse diseases. Although GAS is considered as extracellular pathogen, now accumulated evidences showed that GAS can multiply in intracellular environment. However, the detail mechanisms are still unclear. First, I investigated the effects of known virulence factors and regulators on intracellular multiplication in HMEC-1. The gentamicin protection assay was used to measure the bacterial survival. Wild-type A20 and NZ131 strains and their isogenic mutants including virulence factor speB and regulators luxS, rgg, fasB, lacD.1, and srv were analyzed. The results showed that only rgg mutant had a reduced ability of intracellular multiplication, whereas rgg mutant had higher cytotoxicity which may cause fewer recovered bacteria. Therefore, I could not conclude that rgg is involved in intracellular multiplication. In nga study, SF370 without NADase activity could not multiply in HMEC-1, whereas A20 and NZ131 with NADase activity could. When I complemented the nga gene from NZ131 to SF370, SW959 (SF370+pNZnga), the result not only showed the restored NADase activity but had multiplication ability. However, NZ131 nga isogenic mutant (SW957) reduced the multiplication in HMEC-1. By confocal microscopy and western blotting, LC-3 punctuates were formed in all strains, in the early infection. However, the NADase positive strains recruited LC-3 punctuates which were not found in NADase negative strains after longer infection. Furthermore, the lysotracker staining showed that the strains without NADase activity would be cleaned by acidified autophagolysosome, and these phenomena were recovered by the lysosome inhibitor, balfilomycin A1. In conclusion, my data demonstrated that nga can prevent the clearance of acidified autophagolysosome, suggesting that nga plays an important role in intracellular multiplication in HMEC-1.

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