Molecular Mechanisms Underlying Dendritic Cell Adaptations During Chronic Infection

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ABSTRACT Chronic viral infections represent a major biomedical problem and are characterized by a long-term equilibrium between the pathogen and the immune system. Such equilibrium is enabled by adaptations of immune cells that attenuate selected immune functions to minimize immunopathology while keeping the pathogen in check. Similar immune-adaptations may be detected (often in a transient manner) after acute infections but are only sustained and relevant for pathogen persistence during chronic infections. Thus, studying the mechanisms underlying immune cell adaptations in the context of chronic infections may not only unveil new basic biology of the immune system but could also unlock new therapeutic strategies for alleviating persistently infected individuals. This is best exemplified by the discovery of T cell exhaustion and their inhibition via the inhibitory receptor PD1 during lymphocytic choriomeningitis virus (LCMV) infection in its natural murine host, two findings that were extended to many infections in humans as well as cancer and autoimmune diseases. In addition, we and others have established that Dendritic Cells (DC), which play central roles in immunity, also adapt in the context of chronic viral infections, showing compromised development from bone marrow progenitors, suboptimal maturation and altered cytokine production. To understand the mechanisms underlying DC and their progenitor adaptations, we applied a cutting- edge bioinformatic approach to analyze the transcriptome and epigenome of DC progenitors from LCMV infected mice, and predicted altered activity of several transcription factors (TFs). Among them, we revealed that Glucocorticoid Modulatory Element Binding Protein 1 (Gmeb1) suppresses DC development and maturation while Zinc Finger Protein 524 (Zfp524) regulates cytokine production in vitro. These results provide evidence that Gmeb1 and Zfp524 hold exceptional promise to improve our basic understanding of DC biology. We propose to take advantage of the well-established and sustained DC adaptations during chronic LCMV infection to further explore the novel roles and underlying mechanisms of Gmeb1 and Zfp524. For that, in Aim#1 and #2 we plan to fully establish the roles of Gmeb1 (Aim1) and Zfp524 (Aim 2) in vitro and in vivo, in both uninfected and LCMV infected mice as well as in human DCs. We will determine their downstream target genes and investigate how these TFs' roles on DC regulation relates to the known function of Gmeb1 as an enhancer of glucocorticoid driven gene expression, and to the putative regulation of Zfp524 expression by Aryl- hydrocarbon receptor. Finally, we will study the relationship of Gmeb1 and Zfp524 DC regulation with the roles of type-I-interferons and toll-like-receptor-7 that we reported for DC adaptations after chronic LCMV infection. Our studies will use cutting-edge technology to unveil the molecular mechanisms by which DCs are regulated in the context of a chronic viral infection in vivo. This will significantly increase our basic knowledge of DC biology and unveil new therapeutic targets to harness DCs in infectious and non-infectious diseases.