Shrimp are invertebrates that live in brackish water and, as a result, are very different from vertebrates that live on land. Their morphology and physiology, including their immunology, are highly adapted to their challenging environment. Their barriers against viral attacks are very effective. The cuticle forms a protective plastic-like layer on the outside (the exoskeleton) and inside (the gills and alimentary tract) of the animals. Only small regions are free of cuticula and open to infection: the hepatopancreas and the nephrocomplex. At the level of the hepatopancreas, there is a sieve that allows only small particles (<0.2-0.7µm) to pass. Viruses can cross, but they are mostly eliminated by numerous enzymes (proteases, glycosidases and lipases) and detergents (N-(N-dodecanoylsarcosyl)taurine) produced by the hepatopancreas. Only very resistant viruses, such as parvoviruses, or enveloped viruses (e.g., baculoviruses) that are protected by occlusion bodies can replicate in hepatopancreas cells. The nephrocomplex forms a second vulnerable area through which viruses can enter and replicate. The two valves at the nephropore act as gatekeepers. They firmly close the entire nephrocomplex and protect shrimp from invading pathogens. Only during frequent urination (defense, osmoregulation, masking the feed) does a risk exist that viruses and bacteria may enter. At present, due to a strong selection for growth by breeding companies, deformities may occur leading to malfunctions of the sieve at the hepatopancreas and of the nephropore. This facilitates the entry of pathogens. More emphasis should therefore be placed on selecting for the correct morphology of barriers.

Shrimp do not have an adaptive immunity. Therefore, it does not make sense to develop vaccines in the same way as for vertebrates. It is better to start with a thorough analysis of their strong innate immunity and to search for attractive targets for viral disease control. One important and powerful activity is the phagocytosis of individual pathogen particles or sequestration of large groups of particles by nodulation, followed by intracellular or

extracellular destruction by oxidation by the prophenoloxidase system (melanisation, causing black discoloration). When this occurs in an uncontrolled manner, it may lead to mortality.  In vertebrates, this destruction process is very restricted and occurs only intracellular. Nodulation in vertebrates would be dangerous because it could lead to intravascular clotting and thrombosis, ultimately ending up with necrosis. In vertebrates, massive recruitment of phagocytes can lead to overactivation and collateral damage. Pharmaceutically, this process is blocked by anti-inflammatory drugs. In shrimp, there is a strong interest in stimulating innate immunity, which is contraindicated. More research should therefore be conducted to examine the effects of anti-inflammatory drugs. The recent identification of NK cells in shrimp opens the door to more targeted immunostimulation. One should try to stimulate NK cells specifically rather than phagocytes. Research in this direction should be supported and funded.

As vaccination will most probably never work, alternative approaches should be explored. Gene editing should receive more attention. RNA interference is important in controlling viral infections in invertebrates. This mechanism is induced by the incorporation of viral genetic material into the host’s genome. As this process takes a long time, one should consider shortening this period by editing the viral genome ourselves rather than waiting for this to occur by a combination of natural mutations and selection. At present, this is biotechnologically feasible using CRISPR-Cas. Other possible approaches to control viral infections by gene editing include (i) modifying entry receptors so that they are no longer functional (this is already done in swine), (ii) strengthening the induction of antiviral mechanisms (e.g. pathway activated by toll-like receptors that detect pathogen RNA/DNA molecules and lead to the production of antiviral molecules/activation of antiviral pathways and/or apoptosis, and (iii) introducing foreign genes encoding molecules from adaptive immunity of vertebrates, such as antibodies. In this context, it is important to identify target regions in the host genome where genes can be introduced without having a negative impact on the shrimp physiology. In addition, shrimp should be raised in closed environments, to prevent escapes. At present, efforts are underway in Europe to develop zero-waste farms that are located inland, totally disconnected from the sea, using independent recirculation water systems.