ERC FUNDED PROJECTS

Interferons (IFNs), which are signalling proteins produced by infected cells, are the first line of defence against viral infections. IFNs induce, in infected and neighbouring cells, the expression of hundreds of IFN-stimulated genes (ISGs). The ISGs in turn induce in cells a potent antiviral state, capable of preventing replication of most viruses, including Human Immunodeficiency Virus type 1 (HIV-1) and influenza A virus (FLUAV). Identifying the antiviral ISGs and understanding their mechanisms of action is therefore crucial to progress in the fight against viruses. ISGs playing a role in the antiviral state have been identified, such as human MX1, a well-known antiviral factor able to restrict numerous viruses including FLUAV, and MX2, an HIV-1 inhibitor. Both proteins bind to viral components but their detailed mechanisms of action, as well as the consequences of restriction on the activation of the innate immune system, remain unclear. Moreover, our preliminary work shows that additional anti-HIV-1 and anti-FLUAV ISGs remain to identify. In this context, this proposal seeks an ERC StG funding to explore 3 major aims: 1) unravelling the mechanisms of antiviral action of MX proteins, by taking advantage of their similar structure and engineered chimeric proteins, and by using functional genetic screens to identify their cofactors; 2) investigating the consequences of incoming virus recognition by MX proteins on innate immune signalling, by altering their expression in target cells and measuring the cell response in terms of gene induction and cytokine production; 3) identifying and characterizing new ISGs able to inhibit viral replication with a combination of powerful approaches, including a whole-genome CRISPR/Cas9 knock-out screen. Overall, this proposal will provide a better understanding of the molecular mechanisms involved in the antiviral effect of IFN, and may guide future efforts to identify novel therapeutic targets against major pathogenic viruses.

1 499 794 €

Start date: 2017-12-01, End date: 2022-11-30

Redox chemistry provides the fundamental basis for numerous energy-related electrochemical devices, among which Li-ion batteries (LIB) have become the premier energy storage technology for portable electronics and vehicle electrification. Throughout its history, LIB technology has relied on cationic redox reactions as the sole source of energy storage capacity. This is no longer true. In 2013 we demonstrated that Li-driven reversible formation of (O2)n peroxo-groups in new layered oxides led to extraordinary increases in energy storage capacity. This finding, which is receiving worldwide attention, represents a transformational approach for creating advanced energy materials for not only energy storage, but also water splitting applications as both involve peroxo species. However, as is often the case with new discoveries, the fundamental science at work needs to be rationalized and understood. Specifically, what are the mechanisms for ion and electron transport in these Li-driven anionic redox reactions? To address these seminal questions and to widen the spectrum of materials (transition metal and anion) showing anionic redox chemistry, we propose a comprehensive research program that combines experimental and computational methods. The experimental methods include structural and electrochemical analyses (both ex-situ and in-situ), and computational modeling will be based on first-principles DFT for identifying the fundamental processes that enable anionic redox activity. The knowledge gained from these studies, in combination with our expertise in inorganic synthesis, will enable us to design a new generation of Li-ion battery materials that exhibit substantial increases (20 -30%) in energy storage capacity, with additional impacts on the development of Na-ion batteries and the design of water splitting catalysts, with the feasibility to surpass current water splitting efficiencies via novel (O2)n-based electrocatalysts.

2 249 196 €

Start date: 2015-10-01, End date: 2020-09-30

Understanding the establishment and persistence of bacterial infections in the gut requires integrating an ensemble of factors including bacterial and host components and the presence of other microorganisms. We will capitalize on 25 years of studies on the bacterium Listeria monocytogenes used as a model, to focus on three objectives which will significantly increase our knowledge of the bacterium, of the cell biology of infection and of the epigenetic reprogramming upon infection. Our aims are: - at the bacterial level : to describe for the first time, the proteomic landscape of a bacterium during switch from saprophytism to virulence. We will use a proteogenomic approach together with ribosome profiling, to analyze the translation of the whole transcriptome after bacterial growth in several conditions, including in vivo, in order to barcode all the proteins which play a role in infection. This will open the way to assess the role of 1) small proteins; 2) internal translation initiation sites ; 3) the coupling of transcription and translation. - at the host cell level : To decipher the molecular mechanisms underlying the dynamics and role in infection of host intracellular organelles, starting with mitochondria. - At the host epigenetic level : To explore how the microbe reprograms host transcription and how tolerance to a commensal such as Akkermansia muciniphila differs from responsiveness to a pathogen insult, at the level of histones and mRNA modifications by studying 1) chromatin remodeling, in particular histones modifications during infection ; 2) modifications of the epitranscriptome during Listeria infection and colonization with Akkermansia ; 3) whether there is an epigenetic memory of infection and colonization. This ambitious multidisciplinary project will not only generate new concepts in infection biology but also will unravel fundamental mechanisms in microbiology, cell biology, and epigenetics opening new avenues for further research.

1 147 500 €

Start date: 2015-10-01, End date: 2019-09-30

The main objective nowadays in the field of biomaterials is to design highly performing bioinspired materials learning from natural processes. Importantly, biochemical and physical cues are key parameters that can affect cellular processes. Controlling processes that occur at the cell/material interface is also of prime importance to guide the cell response. The main aim of the current project is to develop novel functional bio-nanomaterials for in vitro biological studies. Our strategy is based on two related projects. The first project deals with the rational design of smart films with foreseen applications in musculoskeletal tissue engineering. We will gain knowledge of key cellular processes by designing well defined self-assembled thin coatings. These multi-functional surfaces with bioactivity (incorporation of growth factors), mechanical (film stiffness) and topographical properties (spatial control of the film s properties) will serve as tools to mimic the complexity of the natural materials in vivo and to present bioactive molecules in the solid phase. We will get a better fundamental understanding of how cellular functions, including adhesion and differentiation of muscle cells are affected by the materials s surface properties. In the second project, we will investigate at the molecular level a crucial aspect of cell adhesion and motility, which is the intracellular linkage between the plasma membrane and the cell cytoskeleton. We aim to elucidate the role of ERM proteins, especially ezrin and moesin, in the direct linkage between the plasma membrane and actin filaments. Here again, we will use a well defined microenvironment in vitro to simplify the complexity of the interactions that occur in cellulo. To this end, lipid membranes containing a key regulator lipid from the phosphoinositides familly, PIP2, will be employed in conjunction with purified proteins to investigate actin regulation by ERM proteins in the presence of PIP2-membranes.

1 499 996 €

Start date: 2011-06-01, End date: 2016-05-31