CXCL14/BRAK: Organization of immune defense at barrier organs

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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.