Antimicrobial resistance (AMR) is a major threat for animal and public health and recognized by Heads of State in the General Assembly of the United Nations as a major issue on global scale. To contain AMR, antimicrobial usage (AMU) should be reduced as this is considered to be the main driver of selection for resistant bacteria. Furthermore, the veterinary use of (highly prioritized) critically important antimicrobials for human medicine should be reduced as much as possible and replaced by less important antimicrobials for human medicine. Preliminary data collected by consortium partners, showed considerable overuse of antimicrobials in the Indonesian poultry production. Scientific research is needed to support an evidence-based transition towards a sustainable poultry production chain with responsible use of antimicrobials. The research questions are i) why, what and how much antimicrobials are used in broiler production in Indonesia, ii) what alternatives for AMU are available iii) is it possible to reduce AMU by introducing tailor made on-farm intervention strategies. The parameters to be measured are reduction in AMU and the change in AMR levels on farms. One of the results of this project will be the development of a ‘best practice’ document to be used (inter)nationally by stakeholders and scientific publications to share the results with the scientific community. The consortium consists of research organisations, a commercial partner and 4 supporting organisations with strong links with the broiler sector in Indonesia. Two stakeholder meetings will be part of this project to ensure close involvement in the development of the intervention and in the end phase to communicate results and best practices to end-users. Several elements of capacity building are one of the pillars of the project. This project contributes to a safe and sustainable poultry food chain in Indonesia and reduces the risks of resistant bacteria for humans.

Viruses employ the host to make new viral particles. Enteroviruses such as poliovirus, coxsackievirus, and rhinovirus hijack cellular proteins in order to build replication organelles, the “virus production factories”. Lipids are critical components of these. We discovered how viral proteins (2B, 2C, and 3A) commonly manipulate the cellular lipid machinery to build replication organelles. Moreover, we identified an inhibitor specific to viral 2C that inhibits replication. In addition, we have obtained a detailed inventory of virus infection changes the abundance and activity of cellular proteins, thereby adjusting a cell to the needs of the virus.

Antimicrobial resistance (AMR) is a major threat for public health and is caused by use of antimicrobials in humans and animals. In Indonesia, high amounts of antimicrobials are used in the poultry sector. As antimicrobials are widely used by farmers without prescription, and they are called to reduce antimicrobial use (AMU), there is a need to know why antimicrobials are used and what alternatives can be offered to prevent production losses and keep animals healthy while reducing AMU. In the NWO-CORNERSTONE project (started April 1st 2019) this will be studied. However, more in-depth knowledge of the infectious diseases (viral and bacterial) that are present on the farms is needed to better understand why specific antimicrobials are used and what alternatives can be offered to prevent these diseases and use antimicrobials responsibly when diseases occur. By using diagnostic tests, this Hestia project investigates the presence of viruses and bacteria on farms included in the CORNERSTONE-study, and when they occur. This knowledge can be used to develop tailored interventions consisting of specific biosecurity (hygiene) measures and vaccination programs. Prevention of these diseases has a huge potential to reduce AMU. The knowledge of this project is not only of value for the participating farmers (n=25), but gives more insight in the bacteria and viruses that typically threaten animal health on Indonesian poultry farms. It can also be used to support other poultry farmers in the poultry-dense areas in Indonesia and countries in the region with comparable poultry production systems, in their sustainable farming.

Understanding and designing molecular structure is core to science and technology. Electron microscopy (EM) enables high-resolution imaging of biological samples to see molecules at the atomic level and visualize them in 3D in of cells and organs. To keep the Netherlands at the forefront of this revolutionary field, we will create a national infrastructure integrating the latest innovations in cryo-EM and volume EM. The infrastructure will offer users tools for cutting-edge sample preparation, data acquisition and analysis, train and expand the EM community in the Netherlands, and pave the way for new discoveries and scientific advances in medicine and technology.

Proteasomes play a dominant role in intracellular protein degradation and thereby regulate many cellular processes. The peptide products, produced as a consequence of proteolysis, may enter the MHC class I antigen processing pathway for display on the cell surface. This allows CD8+ T cells to detect and react to intracellular aberrancies, such as infections. Recently, it was discovered that an unexpected large fraction of peptides, presented by cell surface MHC class I molecules on human cells, are spliced (hybrid) peptides generated by Proteasome-Catalyzed ligation of peptides / ‘Peptide Splicing’ (PCPS). To examine whether spliced peptides are a target of CD8+ T cells responding to infection, we joined forces with the scientists that performed the named study, to develop a reverse immunology-based approach to identify proteasome-generated spliced epitopes. Applying this strategy, we were first to demonstrate that mouse CD8+ T cells elicited by infection with an intracellular bacterium, recognize linear, as well as spliced bacterium-derived epitopes. In this proposal, we aim to apply the unique expertise available in my lab and that of our collaborators to determine to which extent PCPS plays a role in shaping the antigenic landscape on cells infected with intracellular pathogens. We will explore the mechanistic aspects of spliced epitope generation, focusing on the role of a proteasome regulator (PA28) that is upregulated by infection. We will further determine whether the presented spliced, pathogen-derived peptides are a major target of CD8+ T cells, responding to infection. Thereby, we will establish the immunological relevance of PCPS.