Antibiotic resistance is one of the greatest threats to global health, rendering bacterial infections incurable and requiring the development of alternative treatment strategies. A natural weakness of these infectious bacteria is their own toxin-antitoxin systems. If production of the antitoxin stops, the bacteria’s own toxin acts as a molecular poison for the bacteria themselves, leading to self-killing. We aim to exploit this weakness and devise antibiotics of an innovative nature to artificially release these natural bacterial poisons for the treatment of infectious bacteria.

Conquering the coronavirus replication centre Coronaviruses use infected cells to make copies of themselves that propagate infection. To replicate their genomes, coronaviruses hijack cellular membranes to build up specialized replication compartments. These work as control centres to make the process efficient and hide it from antiviral cellular defences. Recently, we discovered a unique protein complex that provides a gate in the membranes of these replication compartments. Here, we plan to decipher how this gate and the replication organelles are built and function, which will be key to devise plans to assault these viral fortresses to block virus replication and disease.

Positive-stranded RNA (+RNA) viruses constitute the largest virus group, which includes intracellular parasites and important pathogens of human, animals, and plants. During infection, +RNA viruses take control of specific intracellular membranes and remodel them into special structures that support the process of RNA-dependent RNA synthesis required to express and replicate the viral genome. At the molecular level, both viral RNA synthesis and membrane-remodelling are driven by a set of viral non-structural proteins, collectively referred to as replicase. Specialized transmembrane replicase subunits can modifiy the membranes and serve as anchoring points for the +RNA viral replication complex. The modified membranes can thus be viewed as viral factories: they are the working environment of the viral replication machinery and, therefore, also the cradle for +RNA virus evolution. This proposal specifically addresses the largely uncharacterized morphogenesis, ultrastructure, function, and dynamics of both the virus-induced membrane modifications and the associated viral enzyme complex. The experimental design combines classical electron microscopy techniques with advanced methods at the leading-edge of technological developments, including electron tomography, cryogenic tomography, energy-filtered electron microscopy and correlative light-electron microscopy. In the proposed project, this armory of tools will be employed to elucidate (i) the three-dimensional structure of +RNA viral factories (ii) the location of the enzyme complex actively engaged in viral RNA-synthesis, and (iii) the ultrastructural dynamics of the virus-induced membrane modifications. Our microscopy approach will be complemented with biochemical and molecular biological studies through established collaborations, together constituting an integral and innovative strategy for the study of +RNA viral factories. The results of this project will provide crucial insight into the mechanisms underlying +RNA virus replication, open new research avenues in the field, and contribute to the development of novel antiviral strategies.

The innate immune system forms the first line of defense against existing and newly-emerging viruses. Detailed insight into the cells, pathways, and molecules that the innate immune system uses to defend us against viruses will help the discovery of novel therapeutic targets to treat infectious diseases. This Symposium will bring together scientists in the field of innate immunity, viral infection, and molecular biology to exchange knowledge on the latest advancements in these fields.

SUMO wrestling autoimmune diseases. The immune system is essential to protect our bodies against infections. B cells produce antibodies, which help to fight bacteria and viruses. However, overactive B cells in our immune system can cause autoimmune diseases. B cell survival and death are critical to maintain the balance of a proper functioning immune system, thereby preventing autoimmunity. In this project, we will study a new anti-cell death signal in B cells that involves small proteins belonging to the SUMO family. We will dissect this SUMO signaling route in B cells and test SUMO inhibitors in the fight against autoimmunity.