CXCL14/BRAK: Organization of immune defense at barrier organs

上皮表面代表宿主与环境之间的界面。它们是病原体的主要入口，并配备了有效的抗感染效应程序。先前，我们证明CXC趋化因子CXCL 14主要在上皮组织中表达，包括皮肤、口腔粘膜以及肠道和泌尿生殖道。几种Toll样受体配体诱导CXCL 14，而EGFR信号传导的激活抑制其表达。与这些发现一致，我们显示在皮肤癌发生过程中CXCL 14的进行性丢失，这表明CXCL 14在上皮部位的免疫防御中具有重要作用。此外，CXCL 14的表达显着下调人乳头瘤病毒（HPV）诱导的尖锐湿疣。相反，我们发现人巨细胞病毒的早期病毒基因负责通过感染细胞中的AP-1活化诱导CXCL 14。与HPV感染上皮细胞并驻留引起病理不同，HCMV需要扩散和传播到肺、肝、骨髓和中枢神经系统。我们的研究结果表明了一系列事件，这些事件始于上皮细胞和成纤维细胞中HCMV诱导的CXCL 14产生，随后单核细胞和树突状细胞的募集，这些单核细胞和树突状细胞被有效感染，成熟，循环并在远处渗出以传播HCMV感染。基于这些数据，很容易推测HCMV可能劫持宿主的效应程序，以协调单核细胞和树突状细胞作为病毒传播的载体。在第二个资助期内，我们将重点关注以下方面：（一）研究病原体用来干扰CXCL 14产生的信号通路。(II)在野生型和CXCL 14缺陷小鼠中使用MCMV和金黄色葡萄球菌感染模型，揭示CXCL 14在上皮表面免疫防御过程中的体内作用。(III)使用表皮生长因子（EGFR）抑制剂厄洛替尼和EGFR缺陷小鼠研究EGFR信号传导在组织皮肤免疫防御中的作用。

Epithelial surfaces represent the interface between the host and the environment. They are primary entry points for pathogens and equipped with efficient anti-infectious effector programs. Previously, we demonstrated that the CXC chemokine CXCL14 is predominantly expressed in epithelial tissues including skin, oral mucosa as well as intestinal and uro-genital tracts. Several Toll-like receptor ligands induced CXCL14 while activation of EGFR-signalling suppressed its expression. In line with these findings, we show the progressive loss of CXCL14 during cutaneous carcinogenesis suggesting an important role for CXCL14 for the immune defense at epithelial sites. Moreover, CXCL14 expression was markedly down-regulated in human papilloma virus (HPV)-induced Condylomata acuminata. Conversely, we showed that early viral genes of human cytomegalovirus are responsible for the induction of CXCL14 through AP-1 activation in infected cells. Different from HPV, which infects epithelial cells and remains resident to cause pathology, HCMV needs to spread and disseminate into lung, liver, bone marrow and the central nervous system. Our findings suggest a cascade of events that starts with HCMV-induced CXCL14 production in epithelial cells and fibroblasts, subsequently the recruitment of monocytes and dendritic cells which get productively infected, mature, circulate and extravasate at distant sites to disseminate HCMV infection. Based on these data, it is tempting to speculate that HCMV may be hijacking the host’s effector program to orchestrate monocytes and dendritic cells as vectors for viral dissemination. During the second funding period, we will focus on the following aspects: (I) Investigate the signalling pathways pathogens utilize to interfere with CXCL14 production. (II) Unravel the in vivo-role of CXCL14 during immune defense at epithelial surfaces using infection models for MCMV and Staphylococcus aureus in wildtype and CXCL14-deficient mice. (III) Investigate the role of epidermal growth factor (EGFR) signalling for the organization of cutaneous immune defense using the EGFR-inhibitor erlotinib and EGFRdeficient mice.