Molecular mechanisms for type-I Interferon dysregulation

Interferons are a group of cytokines released by cells in response to infection with viruses and other infectious agents. Specifically, type-I interferons can be produced by virtually any cell type in an organism in response to viral infections, except for embryonic stem cells and oocytes. In clinical settings, the deregulation of the interferon response is associated to autoimmune diseases, such as lupus and Singleton-Merten syndrome.

Cells detect the presence of viruses through host pattern recognition receptors (PRRs) that identify traits that are uniquely associated with viruses such as viral genomes or double stranded RNA replication intermediates. Upon detection of these viral molecules, the host cell expresses type-I interferons and interferon-stimulated genes to initiate an antiviral response in the infected and neighbouring cells. Importantly, in the context of autoimmunity and interferonopathies this response is activated in the absence of viral infections.

Preliminary data shows that mammalian embryonic stem cells actively silence the type-I interferon response, but the molecular mechanisms underlying this observation have not been identified. Our hypothesis is that suppression of the interferon response in this cellular context is essential to maintain pluripotency and to avoid the catastrophic consequences of inappropriate interferon activation.

In this project, we aim to identify the factors, protein and RNA components, that are essential to silence the type-I interferon response in the human and mouse pluripotent context. Secondly, we will translate these findings to a relevant autoimmune or type-I interferonopathy cellular model and expand the current knowledge for genetic and functional basis of these diseases.