Colineau Lucie, Laabei Maisem, Liu Guanghui, Ermert David, Lambris John D, Riesbeck Kristian, Blom Anna M
Division of Medical Protein Chemistry, Department of Translational Medicine, Faculty of Medicine, Lund University, Malmö, Sweden.
Department of Biology and Biochemistry, University of Bath, Bath, United Kingdom.
Matrix Biol Plus. 2020 Jan 13;6-7:100020. doi: 10.1016/j.mbplus.2020.100020. eCollection 2020 May.
is a major human pathogen that causes a variety of diseases ranging from mild skin and throat infections to fatal septicemia. In severe invasive infections, encounters and interacts with components of the extracellular matrix (ECM), including small leucine rich-proteoglycans (SLRPs). In this study, we report a novel antimicrobial role played by SLRPs biglycan, decorin, fibromodulin and osteoadherin, specifically in promoting the eradication of in a human sepsis model of infection. SLRPs can be released from the ECM and de novo synthesized by a number of cell types. We reveal that infection of human monocytes by induces the expression of decorin. Furthermore, we show that the majority of genetically distinct and clinically relevant isolates interact with SLRPs resulting in decreased survival in blood killing assays. Biglycan and decorin induce TLR2 and TLR4 signaling cascades resulting in secretion of proinflammatory and chemotactic molecules and recruitment of professional phagocytes. Surprisingly, SLRP-mediated elimination of occurs independently of TLR activation. Our results indicate that SLRPs act in concert with human serum, enhancing deposition of complement activation fragments and the classical activator C1q on the bacterial surface, facilitating efficient microbial eradication. Addition of the complement C3 inhibitor compstatin significantly reverses SLRP-induced blood killing, confirming active complement as a key mediator in SLRP-mediated bacterial destruction. Taken together our results add to the functional repertoire of SLRPs, expanding to encompass their role in controlling bacterial infection.
是一种主要的人类病原体，可导致从轻度皮肤和喉咙感染到致命败血症等多种疾病。在严重的侵袭性感染中，它会与细胞外基质（ECM）的成分相遇并相互作用，包括富含亮氨酸的小分子蛋白聚糖（SLRP）。在本研究中，我们报告了SLRP双糖链蛋白聚糖、核心蛋白聚糖、纤调蛋白和骨黏附素发挥的一种新的抗菌作用，特别是在人类败血症感染模型中促进对其的清除。SLRP可以从ECM中释放出来，并由多种细胞类型重新合成。我们发现感染人类单核细胞会诱导核心蛋白聚糖的表达。此外，我们表明，大多数基因不同且临床相关的分离株与SLRP相互作用，导致在血液杀伤试验中的存活率降低。双糖链蛋白聚糖和核心蛋白聚糖诱导TLR2和TLR4信号级联反应，导致促炎和趋化分子的分泌以及专业吞噬细胞的募集。令人惊讶的是，SLRP介导的清除独立于TLR激活。我们的结果表明，SLRP与人类血清协同作用，增强补体激活片段和经典激活剂C1q在细菌表面的沉积，促进有效的微生物清除。添加补体C3抑制剂compstatin可显著逆转SLRP诱导的血液杀伤，证实活性补体是SLRP介导的细菌破坏的关键介质。综上所述，我们的结果增加了SLRP的功能范围，扩展到包括它们在控制细菌感染中的作用。
