革蘭氏陰性螺旋幽門桿菌的感染不僅會造成胃部發炎反應亦會增加胃癌發生的風險。丙型干擾素具有對抗細菌的能力；然而幽門桿菌感染可誘導丙型干擾素表現的增加進而惡化胃部發炎並利用未知的機制抑制丙型干擾素的抗菌作用以逃脫免疫系統攻擊。本研究著重在探討幽門桿菌負向調控丙型干擾素訊息的機制。丙型干擾素的前處理可減緩胃上皮細胞因感染幽門桿菌而表達cytotoxin-associated gene A (CagA)。感染臨床分離的野生型幽門桿菌菌株HP238與J99以及標準菌株ATCC43504會抑制丙型干擾素誘導SATA1的磷酸化以及干擾素調控因子1啟動子的活化作用。然而，熱致死的HP238無法刺激細胞發生以上現象。HP238活菌感染會刺激Src homology-2 domain-containing phosphatase (SHP) 2蛋白質C端上酪氨酸的磷酸化及下游訊息調控MEK及ERK的磷酸化。利用特異性抑制劑和shRNA干擾的方法證實抑制SHP2可以回復HP238感染所導致丙型干擾素抗性。進一步的研究證實基因突變剔除CagA幽門桿菌菌株HP238CagAm感染則無法造成丙型干擾素抗性以及胃上皮細胞發生hummingbird的形變，可以說明CagA在其中調控的重要角色。值得注意的是HP238CagAm仍會造成SHP2的磷酸化；進一步的影像學和生化分析證明CagA會與磷酸化態的SHP2結合，間接促成膜相關結合的磷酸化SHP2，推測在缺乏CagA的協助下HP238CagAm感染所造成的SHP2磷酸化無法有效抑制丙型干擾素的訊息。最後，實驗證明CagA的表現以及活性氧分子的生成共同促成幽門桿菌感染誘導丙型干擾素抗性。這項發現不僅是提供另一種CagA和活性氧分子如何共同調控SHP2活性的選擇性機制，而且也解釋其在幽門桿菌感染導致丙型干擾素抗性的角色。

Helicobacter pylori (H. pylori), a gram-negative spiral bacteria, infection not only induce gastric inflammation but also increase the risk of gastric tumorigenesis. Interferon (IFN)-γ has antimicrobial effects; however, H. pylori infection elevates IFN-γ-mediated gastric inflammation and may suppress IFN-γ signaling as a strategy to avoid immune destruction through an as-yet unknown mechanism. This study was aimed at investigating the mechanism of H. pylori-induced IFN-γ resistance. Pre-treatment of IFN-γ decreased cytotoxin-associated gene A (CagA) expression following H. pylori infection. Post-infection viable, but not heat-killed, clinical isolates of wild-type H. pylori strain HP238 decreased IFN-γ-induced phosphorylation of signal transducers and activators of transcription 1 and promoter transactivation of IFN-regulatory factor 1. HP238 infection caused an increase in the C-terminal tyrosine phosphorylation of Src homology-2 domain-containing phosphatase (SHP) 2 and its downstream signaling of MEK/ERK. Inhibiting SHP2 by using specific inhibitors and shRNA interference reversed HP238-induced IFN-γ resistance. The CagA isogenic mutant strain HP238CagAm failed to induce IFN-γ resistance and morphological change known as hummingbird phenomenon, indicating that CagA regulates these effects. Notably, HP238 and HP238CagAm both caused SHP2 phosphorylation; furthermore, imaging and biochemical analyses demonstrated CagA-mediated membrane-associated binding with phosphorylated SHP2. Without CagA, HP238CagAm infection only did not cause IFN-γ resistance even SHP2 is phosphorylated. CagA-independent generation of reactive oxygen species (ROS) contributed to H. pylori-induced SHP2 phosphorylation and IFN-γ resistance when CagA was concurrently present. This finding not only provides an alternative mechanism for how CagA and ROS co-regulate SHP2 activation but may also explain their roles in H. pylori-induced IFN-γ suppression of IFN-γ signaling.

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