INFLAMATOX

Climate change increases harmful algal blooms and favors the invasion of European coasts by new species producing dangerous toxins, such as the algae Ostreopsis cf. ovata or Vulcanodinium rugosum. The marine toxins produced by these algae pose a serious threat to human health by inducing inflammatory adverse effects such as severe dermatitis and asthma attacks. Among the marine toxins, the family of ovatoxins (OvTXs) produced by Ostreopsis cf. ovata, as well as cyclic imines (CIs) such as portimines or pinnatoxines produced by Vulcanodinium rugosum, have potent inflammatory effects in humans through poorly understood mechanisms. We recently discovered that OvTX and portimine induce pyroptosis and inflammatory cytokine release by activating inflammasomes dependent on NOD-like receptors (NLRs) in human keratinocytes. These new findings highlight NLR proteins as cornerstones in the response of human cells to inflammatory marine toxins. While NLR proteins and pyroptosis are evolutionarily conserved between marine invertebrates and humans, bivalves and cnidarians appear to be rather resistant to marine toxins. The main hypothesis of the INFLAMATOX project is that marine invertebrates have evolved with adaptations in pyroptosis regulation and inflammasome-dependent pathways to become resistant to inflammatory marine toxins while maintaining innate inflammasome-dependent immune responses effective against bacterial pathogens, whereas humans do not possess such adaptations to marine toxins. Therefore, our main goal is to investigate the adaptations of marine invertebrates to marine algal and bacterial toxins in order to identify bio-inspired pharmacological targets and develop therapeutic molecules targeting inflammasome-dependent pathways for human therapy. Our consortium brings together experts in marine toxins and biomolecules, inflammasome signaling and pharmacology in humans, and innate immunity in marine invertebrates. This unique interdisciplinary network of the INFLAMATOX project provides a unique opportunity to investigate the role of NLRs in response to marine and bacterial toxins in phylogenetically distant animals, in order to identify key regulators to target for new anti-inflammatory and anti-toxin drugs for human health. For this purpose, we will contrast the role of NLRs and inflammasomes in two divergent marine invertebrates - C. gigas and E. pallida - and compare their responses to those of human cells when exposed to inflammatory marine algal or vibrio toxins.