The role of chromatin extracellular traps in host defence of fish against pathogens.

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Chromatin, a complex of DNA, RNA and protein, is the material that makes up the nucleus of a cell and serves to store genetic information. However, strong evidence has accumulated that it also has a second function, remarkably as a weapon in defence against bacteria and other microbes. In both mammals and invertebrates, some dedicated immune cells involved in inflammation, expel their chromatin in response to the presence of microbes in a controlled and regulated way to the exterior of the cell. It then billows out, like a cloud, to form a mesh that traps pathogens and kills them by virtue of small antibiotic proteins from the cell cytoplasm that become studded on the fibres. Put simply it is a cell death process that enables an immune cell to continue combatting infectious agents even after it has died. The present project aims to investigate this process in fish, as, despite it being widely regarded as an important immune strategy in humans and other mammals, it has not yet been considered in the context of fish health and protection against infection. Disease is a huge problem in fish farming. It causes significant financial losses to the producers and undesirable suffering for the fish. The problem of disease is also likely to worsen as sea temperature rises through climate change. Despite efforts to develop vaccines for fish over recent decades, many do not provide full protection against infections. This is because of strain variability in the pathogens and the structure of the 'memory' component of the fish's immune system that is responsible for producing long-lived antibodies. Instead, fish rely heavily on inflammation, or 'innate' (i.e. inborn) processes, such as phagocytosis (bacteria-eating) and production of natural antibiotic proteins, to protect themselves. Therefore the innate system of fish is an important target for preventing and controlling infection. The proposed research will be directed at Atlantic salmon, as this is the major aquaculture species in the UK, with many fish farms located in Scotland. The work will use in vitro (i.e. cell culture) methods to assess which inflammatory cells in salmon deploy chromatin to kill pathogens, how strong the responses of these cells are and how efficiently pathogens are killed on the chromatin nets. A range of fish pathogens known to cause serious and, for the producers, devastating, diseases in their stock animals will be used in these experiments. These pathogens also include representative types of different microbial groups, so it should be possible to discover if some are able to block, evade or escape chromatin entrapment. To investigate the likely impact of water temperature on this aspect of the fish host defences, the work will compare the strength of the chromatin release response and the efficiency of pathogen killing by cells sampled from fish that have been acclimated to different water temperatures ranging from 9 to 19 degrees Celsius. The highest value in this range covers temperatures experienced by farmed salmon at some sites in Scotland where sea temperatures have already risen, but will be more commonly encountered if coastal water temperatures increase by 2 degrees Celsius, as predicted by some climate change models. This part of the project will help to inform us if farmed fish will become more susceptible to disease under future climatic conditions. The research will generate new information about the importance of a highly novel immune process in fish and thus enable us understand better how pathogens and their host interact. The work may further underpin the development of new compounds, feed additives or strategies to limit the problem of disease in aquaculture.