A role for TLR4 in Clostridium difficile infection and the recognition of surface layer proteins.
A role for TLR4 in Clostridium difficile infection and the recognition of surface layer proteins.
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DOI：
10.1371/journal.ppat.1002076
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发表时间：
2011-06
期刊：
影响因子：
6.7
通讯作者：
Loscher CE
中科院分区：
文献类型：
--
作者：
Ryan A;Lynch M;Smith SM;Amu S;Nel HJ;McCoy CE;Dowling JK;Draper E;O'Reilly V;McCarthy C;O'Brien J;Ní Eidhin D;O'Connell MJ;Keogh B;Morton CO;Rogers TR;Fallon PG;O'Neill LA;Kelleher D;Loscher CE
艰难梭菌是人类抗生素相关性腹泻(AAD)和伪膜性结肠炎的病原体。表面层蛋白(SLP)在本病中的作用尚未得到充分研究。这项研究的目的是研究SLP在艰难梭菌识别和随后的免疫系统激活中的作用。研究SLP对骨髓来源的树突状细胞(DC)产生炎性细胞因子、细胞表面标志的表达及其产生辅助性T细胞(Th)反应的能力。从C3H/HEN和C3H/HeJ小鼠分离的DC用来检测TLR4是否识别SLP。在TLR4缺陷小鼠中检测TLR4在感染中的作用。SLPS可诱导DC成熟，其特征是产生IL-12、肿瘤坏死因子α和IL-10，并表达MHCⅡ类分子、CD40、CD80和CD86。此外，SLP激活的DC产生产生干扰素γ和IL-17的Th细胞。SLP不能激活TLR4突变C3H/HeJ小鼠的DC，也不能诱导随后的Th细胞反应。TLR4−/−和MYD88−/−小鼠对艰难梭菌感染比野生型小鼠更敏感，而TRIF−/−小鼠不敏感。此外，SLP激活了TLR4下游的NFκB，但不能激活IRF3。我们的结果表明，从艰难梭菌中分离的SLP可以激活天然免疫和获得性免疫，这些作用是由TLR4介导的，TLR4在艰难梭菌的实验性感染中具有功能作用。这表明SLP在免疫系统识别艰难梭菌方面发挥了重要作用。艰难梭菌是医院患者抗生素相关性腹泻的主要原因，严重时可导致假膜性结肠炎甚至死亡。目前关于免疫系统如何识别这种病原体以及清除病原体所需的关键机制的信息有限。艰难梭菌表达由表面层蛋白(SLP)组成的准晶表面蛋白阵列，称为S层。它们位于细菌外表面，表明它们可能参与了病原体的免疫识别。在这项研究中，我们证明这些SLP是由Toll样受体4(TLR4)识别的。SLP激活TLR4导致树突状细胞成熟，随后激活T辅助细胞反应，这在清除病原体方面是重要的。此外，使用艰难梭菌感染的小鼠模型，我们表明，在没有TLR4的情况下，小鼠的感染严重程度增加。这是首次证明TLR4在艰难梭菌相关感染中的作用，并表明SLP在产生清除这种细菌所需的免疫反应中发挥了重要作用。
Clostridium difficile is the etiological agent of antibiotic-associated diarrhoea (AAD) and pseudomembranous colitis in humans. The role of the surface layer proteins (SLPs) in this disease has not yet been fully explored. The aim of this study was to investigate a role for SLPs in the recognition of C. difficile and the subsequent activation of the immune system. Bone marrow derived dendritic cells (DCs) exposed to SLPs were assessed for production of inflammatory cytokines, expression of cell surface markers and their ability to generate T helper (Th) cell responses. DCs isolated from C3H/HeN and C3H/HeJ mice were used in order to examine whether SLPs are recognised by TLR4. The role of TLR4 in infection was examined in TLR4-deficient mice. SLPs induced maturation of DCs characterised by production of IL-12, TNFα and IL-10 and expression of MHC class II, CD40, CD80 and CD86. Furthermore, SLP-activated DCs generated Th cells producing IFNγ and IL-17. SLPs were unable to activate DCs isolated from TLR4-mutant C3H/HeJ mice and failed to induce a subsequent Th cell response. TLR4−/− and Myd88−/−, but not TRIF−/− mice were more susceptible than wild-type mice to C. difficile infection. Furthermore, SLPs activated NFκB, but not IRF3, downstream of TLR4. Our results indicate that SLPs isolated from C. difficile can activate innate and adaptive immunity and that these effects are mediated by TLR4, with TLR4 having a functional role in experimental C. difficile infection. This suggests an important role for SLPs in the recognition of C. difficile by the immune system. Clostridium difficile is the leading cause of antibiotic-associated diarrhoea among hospital patients and in severe cases can cause pseudomembranous colitis and even death. There is currently limited information regarding how this pathogen is recognised by the immune system and the key mechanisms necessary for clearance of the pathogen. C. difficile expresses a paracrystalline surface protein array, termed an S-layer, composed of surface layer proteins (SLPs). Their location on the outer surface of the bacteria suggests that they may be involved in immune recognition of the pathogen. In this study we demonstrate that these SLPs are recognised by toll-like receptor 4 (TLR4). Activation of TLR4 by SLPs resulted in maturation of dendritic cells and subsequent activation of T helper cell responses which are known to be important in clearance of pathogens. Furthermore, using a murine model of C. difficile infection we show that mice display increased severity of infection in the absence of TLR4. This is the first study to demonstrate a role for TLR4 in infection associated with C. difficile and suggests an important role for SLPs in the generation of the immune response necessary for clearance of this bacterium.
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作者：
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DOI：
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