Constitutive and Inflammation-Dependent Antimicrobial Peptides Produced by Epithelium Are Differentially Processed and Inactivated by the Commensal Finegoldia magna and the Pathogen Streptococcus pyogenes
Constitutive and Inflammation-Dependent Antimicrobial Peptides Produced by Epithelium Are Differentially Processed and Inactivated by the Commensal Finegoldia magna and the Pathogen Streptococcus pyogenes
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DOI：
10.4049/jimmunol.1004179
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发表时间：
2011-10-15
影响因子：
4.4
通讯作者：
Egesten, Arne
中科院分区：
文献类型：
--
作者：
Frick, Inga-Maria;Nordin, Sara L.;Egesten, Arne
上皮衬里作为物理屏障并产生抗菌肽（AMP）以维持宿主完整性。例子是杀菌蛋白中期因子（MK）和BRAK/CXCL 14，其组成性地产生于皮肤表皮层中，其中厌氧革兰氏阳性球孢子菌Finegoldia magna驻留。因此，这种细菌可能会遇到MK和BRAK/CXCL 14，使这些分子可能对其栖息地构成威胁。在这项研究中，我们表明，MK表达在炎症过程中上调，伴随着强烈下调的BRAK/CXCL 14，导致改变抗菌条件。MK、BRAK/CXCL 14以及炎症依赖性抗微生物β-防御素人β-防御素（hBD）-2和hBD-3均显示出对两种F. magna和毒性病原体化脓性链球菌在相似的浓度。SufA是F.大，降解MK和BRAK/CXCL 14，但不是hBD-2或hBD-3。在赖氨酸和精氨酸残基处观察到裂解，这是AMP的氨基酸特征。MK和BRAK/CXCL 14的中间体SufA降解片段对S.化脓性比F.大，从而促进后者的生存。与此相反，S.化脓菌迅速降解所有研究的AMP。FAF和SIC蛋白是由F. magna和S.化脓性链球菌分别中和MK和BRAK/CXCL 14的抗菌活性，蛋白质FAF是最有效的。通过免疫电子显微镜进行的定量和共定位证明了体内和离体样品中分子的显著水平和相互作用。这些发现反映了一种永久性的寄生虫和一种致命的病原体所使用的策略，后者在侵袭性疾病的有限时间过程中起作用。免疫学杂志，2011，187：4300-4309。
Epithelial linings serve as physical barriers and produce antimicrobial peptides (AMPs) to maintain host integrity. Examples are the bactericidal proteins midkine (MK) and BRAK/CXCL14 that are constitutively produced in the skin epidermal layer, where the anaerobic Gram-positive coccoid commensal Finegoldia magna resides. Consequently, this bacterium is likely to encounter both MK and BRAK/CXCL14, making these molecules possible threats to its habitat. In this study, we show that MK expression is upregulated during inflammation, concomitant with a strong downregulation of BRAK/CXCL14, resulting in changed antibacterial conditions. MK, BRAK/CXCL14, and the inflammation-dependent antimicrobial beta-defensins human beta-defensin (hBD)-2 and hBD-3 all showed bactericidal activity against both F. magna and the virulent pathogen Streptococcus pyogenes at similar concentrations. SufA, a released protease of F. magna, degraded MK and BRAK/CXCL14 but not hBD-2 nor hBD-3. Cleavage was seen at lysine and arginine residues, amino acids characteristic of AMPs. Intermediate SufA-degraded fragments of MK and BRAK/CXCL14 showed stronger bactericidal activity against S. pyogenes than F. magna, thus promoting survival of the latter. In contrast, the cysteine-protease SpeB of S. pyogenes rapidly degraded all AMPs investigated. The proteins FAF and SIC, released by F. magna and S. pyogenes, respectively, neutralized the antibacterial activity of MK and BRAK/CXCL14, protein FAF being the most efficient. Quantitation and colocalization by immunoelectron microscopy demonstrated significant levels and interactions of the molecules in in vivo and ex vivo samples. The findings reflect strategies used by a permanently residing commensal and a virulent pathogen, the latter operating during the limited time course of invasive disease. The Journal of Immunology, 2011, 187: 4300-4309.