綠膿桿菌為一伺機性感染的病原菌，經由傷口、尿道、呼吸道及眼角膜等途徑感染免疫缺陷的病患，造成急性或慢性的感染。綠膿桿菌會分泌數種毒力因子，例如廣泛被探討彈性蛋白酶 B，其在細菌感染過程中扮演重要角色。然而，外分泌蛋白酶彼此之間的修飾以及對其他外分泌蛋白之調節尚未全盤明瞭。在本研究中，我們測定綠膿桿菌 B136-33 及其蛋白酶突變株 ΔpaaP、ΔlasA、ΔlasB 及 ΔprpL 之生長、分解受質蛋白、刺激免疫反應、附著、穿透細胞之能力等，亦解析外分泌蛋白體以了解蛋白酶 PaaP、LasA、LasB 及 PrpL 對於外分泌蛋白之修飾及調節所扮演的角色。結果顯示，突變株 ΔlasB 及 ΔprpL 在低營養培養基中的生長顯著地較為緩慢。突變株 ΔlasB 形成生物膜之能力以及分解數種受質蛋白 (如層黏蛋白、巢蛋白、運鐵蛋白、α-2 巨球蛋白等) 的能力皆明顯下降。四株蛋白酶突變株貼附及穿透細胞的能力皆顯著減弱。以細菌上清液刺激巨噬細胞誘發免疫反應方面，ΔlasB刺激巨噬細胞分泌較多的 IL-6 而 ΔprpL 則使巨噬細胞分泌較少的 IL-6。比較蛋白酶突變株與野生株之外分泌蛋白組成及其含量，ΔpaaP、ΔlasA、ΔlasB 及 ΔprpL 分別有 3、37、60 及 38 種蛋白質的含量與野生株不同。其中，與細菌生長及調節宿主免疫蛋白相關的蛋白 (如：免疫調節金屬蛋白酶、胜肽酶、參與能量合成之酵素等) 在突變株 ΔpaaP、ΔlasA、ΔlasB 及 ΔprpL 中的含量皆明顯減少。綜合以上結果，綠膿桿菌之蛋白酶除了是重要的毒力因子外，也在調節本身的外分泌蛋白及宿主的蛋白質扮演重要的角色。本研究除了進一步瞭解綠膿桿菌蛋白酶的功能，並能提供資訊以尋找可降低毒性蛋白酶活性的物質，減緩綠膿桿菌感染的程度。

Pseudomonas aeruginosa is an opportunistic pathogen that can cause both acute and chronic infections in immunocompromised patients through wound, urethra, respiratory tract and cornea. P. aeruginosa can secrete several virulence factors such as the well-known elastase B that plays an important role in bacterial infection. However, the proteolytic processing of the secretome of P. aeruginosa remains largely unknown. In this study, we examined several physiology and pathogenesis proportion of P. aeruginosa B136-33, ΔpaaP, ΔlasA, ΔlasB and ΔprpL, such as growth rate, ability of substrate degradation, stimulation of the immune response, and bacterial adhesion to and penetration into epithelial cells. We also determined the secretome of P. aeruginosa wild type strain and protease mutant strains to understand how PaaP, LasA, LasB and PrpL modulate extracellular proteins. The result showed that ΔlasB and ΔprpL grew at a slower rate in low nutrition medium. The protease mutant ΔlasB displayed a decreased ability of biofilm formation and degradation of several substrates (eg, laminin, entactin, alpha-2-macroglobulin and Transferrin). Bacterial adhesion to and penetration into Int 407 cell were significantly decreased in ΔpaaP, ΔlasA, ΔlasB, and ΔprpL. In the aspect of immune response, macrophage secreted higher concentration of IL-6 after ΔlasB supernatant stimulated, and lower concentration of IL-6 after ΔprpL supernatant stimulated. According to the result of secretome analysis, protease mutant strain ΔpaaP, ΔlasA, ΔlasB, and ΔprpL displayed 3, 37, 60 and 38 secreted proteins, which were different from that of the wild type strain, respectively. The proteins associated with bacterial growth and regulating host immune proteins were significantly decreased in four mutant strains, such as immunomodulatory metalloproteinases, peptidases and enzymes involved in energy synthesis. Taken together, P. aeruginosa proteases are not only important role of virulence factors, but important role in proteolytic processing of the secretome and modulating host proteins. These findings can lead to comprehensive understanding of the role of P. aeruginosa proteases and providing information for searching targets to reduce P. aeruginosa infection.

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