PROJECTS

Antiviral Innate Immunity of ES cells

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

We are interested in deciphering the mechanisms that control the activation of the type-I interferon response in the differentiated and pluripotent context. We are also interested in understanding how pluripotent cells defend from viruses.

Witteveldt J, Knol L, Macias S (2019) MiRNA-deficient mouse embryonic stem cells acquire a functional Interferon response. eLife pii: e44171. doi: 10.7554/eLife.44171

Mueller F, Witteveldt J, Macias S (2024) Antiviral defence mechanisms during early mammalian development. Viruses 16(2), 173

Translational control of the type I interferon response

One highly effective cellular response to viral infections is the global shutdown of translation known as host shut-off. This response aims at delaying viral replication through preventing viral mRNAs from creating new infectious particles. This effect is mediated by phosphorylation of Eukaryotic initiation factor 2 alpha (eIF2α) by the double stranded RNA binding kinase PKR. The underlying mechanisms of this process are poorly understood, since this effect on translation is not global and ISGs can still be translated during this response. Certain ISGs are known to escape host shut-off through internal ribosome entry site (IRES) dependent translation, however, not all ISGs contain IRES sites.

We are currently investigating host cellular factors that are necessary to efficiently translate type-I interferon mRNAs and other ISGs. By employing polysome profiling we are characterizing all the pools of mRNAs whose translation is either positively or negatively regulated by the IFN response in order to bioinformatically identify special features in these mRNAs that will predict their translational behaviour.

Watson S, Bellora N, Macias S (2019) ILF3 is essential to establish the antiviral type I interferon gene expression program. Nucleic Acids Research pii: gkz1060. doi: 10.1093/nar/gkz1060

Role of RNA processing enzymes in human disease

Many human diseases, including cancer, correlate with mutations in RNA processing enzymes, but it is still unclear if defective RNA processing is causative of the disease.

Using genome-wide approaches and CRISPR, we are modelling some of these mutations in human cellular models to characterize the molecular consequences of these mutations in cell physiology but also gene expression. In this manner, we are hoping to provide a molecular landscape of the main pathways or molecules malfunctioning in the disease with the aim of identifying novel therapeutic targets.