Sonesson Andreas, Nordahl Emma Andersson, Malmsten Martin, Schmidtchen Artur
Division of Dermatology and Venereology, Department of Clinical Sciences, Lund University, 221 84 Lund, Sweden.
Int J Pept. 2011;2011:761037. doi: 10.1155/2011/761037. Epub 2011 Sep 14.
In both immunocompromised and immunocompetent patients, Candida and Malassezia are causing or triggering clinical manifestations such as cutaneous infections and atopic eczema. The innate immune system provides rapid responses to microbial invaders, without requiring prior stimulation, through a sophisticated system of antimicrobial peptides (AMPs). High molecular weight kininogen (HMWK) and components of the contact system have previously been reported to bind to Candida and other pathogens, leading to activation of the contact system. A cutaneous Candida infection is characterized by an accumulation of neutrophils, leading to an inflammatory response and release of enzymatically active substances. In the present study we demonstrate that antifungal peptide fragments are generated through proteolytic degradation of HMWK. The recombinant domain 5 (rD5) of HMWK, D5-derived peptides, as well as hydrophobically modified D5-derived peptides efficiently killed Candida and Malassezia. Furthermore, the antifungal activity of modified peptides was studied at physiological conditions. Binding of a D5-derived peptide, HKH20 (His(479)-His(498)), to the fungal cell membrane was visualized by fluorescence microscopy. Our data disclose a novel antifungal activity of D5-derived peptides and also show that proteolytic cleavage of HMWK results in fragments exerting antifungal activity. Of therapeutic interest is that structurally modified peptides show an enhanced antifungal activity.
在免疫功能低下和免疫功能正常的患者中，念珠菌和马拉色菌都会引发临床表现，如皮肤感染和特应性皮炎。先天性免疫系统通过一套复杂的抗菌肽（AMP）系统，对微生物入侵者做出快速反应，无需预先刺激。高分子量激肽原（HMWK）和接触系统的成分此前已被报道可与念珠菌及其他病原体结合，从而激活接触系统。皮肤念珠菌感染的特征是中性粒细胞积聚，导致炎症反应并释放酶活性物质。在本研究中，我们证明了抗真菌肽片段是通过HMWK的蛋白水解降解产生的。HMWK的重组结构域5（rD5）、D5衍生肽以及疏水修饰的D5衍生肽均能有效杀死念珠菌和马拉色菌。此外，还在生理条件下研究了修饰肽的抗真菌活性。通过荧光显微镜观察到一种D5衍生肽HKH20（His(479)-His(498)）与真菌细胞膜的结合。我们的数据揭示了D5衍生肽的一种新型抗真菌活性，同时表明HMWK的蛋白水解切割会产生具有抗真菌活性的片段。具有治疗意义的是，结构修饰的肽显示出增强的抗真菌活性。
