LiceVault - implementing a model organism for studying vault function and application as smart adjuvant for fish vaccination

Ever since early life-scientists looked through microscopes in the 17th century, they have strived to understand the basic building blocks of life. Our knowledge about the workings of cells and their parts has become more and more comprehensive over time. Vaults are a remarkable exception as they represent one of the last mysterious cell parts. They were called vaults after their similarity to gothic architecture. Vaults are large structures, about three times the size of a ribosome and present in most animal cells. Their 3-dimensional structure is known, but we have very limited understanding of their function. One of the first presumptions was that vaults play a role in cancer cell resistance towards chemotherapy. Later, it was found that amount of vault is correlated to different stresses, like lack of oxygen, and toxins. Researchers have also suggested that vaults are intracellular transporters. Comparing different genomes, we found that the Atlantic salmon louse has even more genes (i.e. three paralouges) for vaults than for example humans. The salmon louse is an ectoparasite and causes severe problems and losses to fish farming and might threaten wild salmon by feeding on its blood and skin. Strict control measures are put in place if numbers get too high. These range from pesticides to mechanical delousing and cleaner fish. Salmon lice are very adaptive and have developed resistance against most chemicals. Within the project, we will study the function of vaults in the salmon louse and whether they contribute to stress tolerance or drug resistance. Our investigation so far indicates that both the localization and function of vault may be different from what has been expected before. Our ongoing efforts are therefore focused on verifying this by several independent methods. In addition, we are now finalizing a phylogenetic investigation where all available genomes have been searched for Vault (i.e. MVP) sequences and compared.

Vaults are about the last enigmatic organelles in Eukaryotes. With approximately three times the size of a ribosome, vaults are also the largest ribonucleoprotein complexes known to date, largely conserved in sequence and structure, and present in most eukaryote lineages. Engineered vaults also have a practical application as smart adjuvants in vaccination. Because of their ancient evolutionary origin, most of the existing hypotheses are unlikely to point to the primordial function of vaults, and therefore, despite cellular slime molds, but absent in some the most important model organisms such as yeast, the fruit fly, nematodes and plants. Since 30 years, the vault and its function have been the subject of many studies. One of the first studies implicated vaults in multi-drug resistance in human cancer; other proposed functions are stress response, intracellular signaling and transport, and innate immunity. Despite all efforts, the basal cellular function of vaults remains elusive. One of the reasons for the failure to assign a clear function to vaults could be the lack of a suitable model organism. Therefore, we propose to establish the Atlantic salmon louse as new model organism, utilizing some of its unique features of life-style, genome organization and evolution. The salmon louse is a major blood-feeding ectoparasite of fish; its genome has been recently sequenced and vault proteins have undergone recent gene duplication. Its reduced genome has the lowest number of detoxification genes ever recorded, lacks peroxisomes and heme degradation, though as a blood-feeding parasite it is exposed to many stressors, e.g. free heme, pesticides, including hydrogen peroxide. Salmon lice have a large environmental and economical impact. Resistances have been reported against all pesticides used so far, and a vaccine against the salmon louse is therefore highly desirable, and we will explore the application of vaults as smart adjuvants for vaccination of fish.