CXCL14/BRAK: Organization of immune defense at barrier organs

上皮表面代表了宿主和环境之间的界面。它们是病原体的主要入口点，并配备了有效的抗感染效应器程序。以前，我们证明CXC趋化因子CXCL14主要在皮肤、口腔粘膜以及肠道和生殖道等上皮组织中表达。几种Toll样受体配体可诱导CXCL14的表达，而EGFR信号通路的激活则抑制其表达。根据这些发现，我们发现CXCL14在皮肤癌变过程中逐渐丢失，这表明CXCL14在上皮部位的免疫防御中发挥着重要作用。此外，在人乳头瘤病毒(HPV)诱导的尖锐湿疣中，CXCL14的表达显著下调。相反，我们发现人类巨细胞病毒的早期病毒基因通过激活AP-1在感染细胞中诱导了CXCL14。与HPV不同的是，HPV感染上皮细胞并停留在一起导致病理变化，而HCMV需要传播和扩散到肺、肝、骨髓和中枢神经系统。我们的发现表明，一系列事件始于HCMV诱导上皮细胞和成纤维细胞产生CXCL14，随后单核细胞和树突状细胞被招募，这些细胞获得生产性感染，成熟，循环并渗出到远处传播HCMV感染。基于这些数据，人们很容易推测，HCMV可能劫持了宿主的效应器程序，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，我们将重点关注以下几个方面：(I)调查病原体干扰CXCL14产生的信号通路。(Ii)利用野生型和CXCL14缺陷小鼠的MCMV和金黄色葡萄球菌感染模型，揭示CXCL14在上皮表面免疫防御中的体内作用。(Iii)研究表皮生长因子(EGFR)信号在EGFR抑制剂erlotinib和EGFR缺陷小鼠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.