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Adaptive immunity in prokaryotes: how Bacteria do not forgive and do not forget their enemies

Periodic Reporting for period 3 - REMEMBER (Adaptive immunity in prokaryotes: how Bacteria do not forgive and do not forget their enemies)

Reporting period: 2018-03-01 to 2019-08-31

Microbes in natural ecosystems are under constant evolutionary pressure from viruses. To survive in this hostile environment microbes have evolved an adaptive immune system called CRISPR-Cas. The REMEMBER project sets out to determine the mechanism of the enigmatic process of memory formation in CRISPR against heavily mutated viruses that infect bacteria. Using a combination of genetic, biochemical and structural approaches, I will investigate the hypothesis that perfectly matching and degenerate targets trigger simultaneous virus DNA degradation and memory updates. We will also test how CRISPR systems prevent autoimmunity: how do bacteria prevent accidental targeting of themselves, with lethal consequences as a result. The knowledge acquired will help us develop better strategies to use bacteriophages as alternatives for antibiotics.
Project REMEMBER has focused on how CRISPR systems keep their memory up to date. Nowadays CRISPR is synonymous with genome editing with Cas9, but CRISPR is much more complex and sophisticated than that. Bacteria immunize themselves against viruses using CRISPR and this step is not well understood. You may consider this step to be comparable to a vaccination in which our bodies are exposed to weakened viruses to trigger an immune response that protects us from infection by a real virus. The challenge for immune systems, however, is to deal with ever changing viruses. We found out that CRISPR can update its immunological memory by coupling inefficient immune reaction to new immunizations. This way the response will be amplified and the bacterium keeps track of the ever-mutating virus.
The project is beginning to yield results that allow us to predict if bacteria will rapidly become resistant to bacteriophages. More research is needed to further the project.