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Abstract African lungfish estivate every dry season to survive unfavorable environmental conditions. The estivation process is associated with a drastic remodeling of the skin characterized by severe inflammation, granulocyte infiltration, epithelial damage and stem cell depletion which ultimately lead to formation of a cocoon with potent antimicrobial functions. We recently identified a novel toxin molecule that can be detected in the lungfish mucus and cocoon using proteomics. There are two genes in the African lungfish genome encoding for this toxin, one with six exons and the segmented duplicated gene with five exons. The toxin is also found in the Australian lungfish genome as a single exon molecule but appears to be lost in South American lungfish. Our studies show that dermal stem cells express this toxin at the steady state. Upon estivation, toxin mRNA levels are upregulated up to 200-fold and immunofluorescence microscopy shows it co-localizes with extracellular trap markers. 3D structure modeling predicts a pore-forming delta-endotoxin with potential insecticide functions. Current experiments are trying to elucidate the biological roles of this new toxin in the lungfish skin during freshwater and estivating stages. 

Detecting danger is key to the survival and success of all species. Animal nervous and immune systems cooperate to optimize danger detection. Preceding studies have highlighted the benefits of bringing neurons into the defense game, including regulation of immune responses, wound healing, pathogen control, and survival. Here, we summarize the body of knowledge in neuroimmune communication and assert that neuronal participation in the immune response is deeply beneficial in each step of combating infection, from inception to resolution. Despite the documented tight association between the immune and nervous systems in mammals or invertebrate model organisms, interdependence of these two systems is largely unexplored across metazoans. This review brings a phylogenetic perspective of the nervous and immune systems in the context of danger detection and advocates for the use of non-model organisms to diversify the field of neuroimmunology. We identify key taxa that are ripe for investigation due to the emergence of key evolutionary innovations in their immune and nervous systems. This novel perspective will help define the primordial principles that govern neuroimmune communication across taxa.