抗菌胜肽刺激轉糖鏈球菌抵抗人類嗜中性白血球的毒殺

Abstract

感染性心內膜炎是心血管系統的感染性疾病，有很高的死亡率。共生於人類口腔中的轉糖鏈球菌能伺機感染心臟瓣膜缺損的病人，引發心內膜炎。對轉糖鏈球菌而言，逃避免疫監控並存活於宿主的循環系統中是引發心內膜炎很重要的致病因素。陽性抗菌胜肽是先天性免疫系統的效應分子，能幫助宿主清除病菌，其主要分布於皮膚、黏膜、唾液與吞噬細胞的顆粒中，其特性是帶正電性並兩性的結構，會受細菌負電表面吸引而作用在細胞膜上，並進而殺死細菌。人類唾液中富含許多抗菌胜肽，如histatins與β-defensins。在本研究中，我們發現以人類histatin-5與polymyxin B刺激轉糖鏈球菌，能有效提高其在人類嗜中性白血球中的存活能力。並且histatin-5與polymyxin B皆能降低轉糖鏈球菌對過氧化氫的敏感度，轉糖鏈球菌可能因此降低對嗜中性球內活性氧分子的敏感度。有趣的是，血漿中富含的鈣離子能降低polymyxin B所提高轉糖鏈球菌在嗜中性球與過氧化氫存在下的存活率，但對histatin-5卻不能，且在ciaH突變株中，鈣離子不會降低polymyxin B的效果。根據以上的研究結果推測，轉糖鏈球菌可能利用唾液中的histatin-5提高在宿主循環系統中的存活，然後血漿中的鈣離子能競爭抗菌胜肽，調節轉糖鏈球菌適應循環系統的血液環境。

Infective endocarditis (IE) is an infectious disease of the cardiovascular system, and carries a high mortality rate. Streptococcus mutans, a commensal in the human oral cavity, is an opportunistic pathogen to cause IE. For S. mutans, to escape the immune surveillance and survive in the host circulation are important virulence traits to cause IE. Cationic antimicrobial peptides（CAMPs）are the innate immune effectors for host to clear the pathogen. They generally exist in the skin, epithelial surfaces, saliva and within the granules of phagocytic cells. CAMPs share common features that have a net positive charge and an amphipathic structure, which promote CAMPs to interact with negatively charged bacterial membranes and kill the pathogen. There are amount of CAMPs in the saliva, such as histatins and β-defensins but these CAMPs has limited effect on Gram positive pathogen, including S. mutans. In this report, we found that the CAMPs, histatin-5 and polymyxin B, could enhance S. mutans survival within human neutrophils. In addition, both histatin-5 and polymyxin B can lower bacteria sensitivity to H2O2, which mimic the ROS response in the phagosome of neutrophils. Interestingly, the calcium ions, which is rich in the plasma, could lower the effect of polymyxin B-enhanced bacterial survival in the presence of neutrophils and H2O2, but can not lower the effect of histatin-5. In ciaH mutant, calcium ions cannot compensate for the effect of polymyxin B. The data presented suggest that histatin-5 in saliva may utilized by S. mutans to enhance survival in circulation and calcium ions in plasma may compete with CAMPs, which shapes S. mutans to adapt to blood circulation environment.