Background: In 2017, World Health Organization reinstated snakebite envenoming to its priority list of neglected tropical diseases. In France, concern is related to the fashion of maintaining exotic snakes as pets, whereas Bothrops sp. are responsible for life-threatening envenomations in French guyanan and Martinique. Local signs include pain, edema, and soft tissue necrosis, whereas systemic effects are incoagulable blood, spontaneous bleeding, and major endothelial dysfunction. Bothrops antivenoms are the only specific treatment to counteract envenoming, whereas their clinical efficacy has been rchallenged. Specific rationale of the research program: In most cases, chosen antivenom starts hours after the snake accident; thus, tissue inflammatory process is well advanced at the time of immunotherapy. Despite potent inhibition of circulating toxins by antivenoms, Bothrops snakebite can trigger overwhelming systemic inflammatory host response (SIRS), leading to multiple organ system failure and death. Central to sterile SIRS are recognition of “sensing danger” motifs such tissue damage-associated molecular pattern molecules (DAMPs). DAMPs induce inflammation through recognition by Toll like receptors (TLRs) and NOD-like receptors (NLRs), activating transcription factors and inflammation. Hypothesis of the research program: We state that Bothrops snakebites can induce overwhelming SIRS triggered by venom-associated molecular patterns (VAMPs) and DAMPs signaling. Regarding “danger motifs”, DAMPs release from mitochondria (mtDAMPs) is of critical importance due to their ancestral microbial origin. We state that mtDAMPs may be released from either injured bitten tissues or secondary to increased cell membrane permeability of target organs in response to exposure to Bothrops venom toxins. In addition, mitochondrial dysfunction elicited by severe envenomations will disrupt fine tune regulation of innate immune response through mechanisms involving oxidative stress, cardiolipin externalization, and impaired mitophagy. Preventing mitochondrial dysfunction by mitochondria-targeted antioxidants would thus able to improve severe Bothrops envenomation. Results and discussion: Our results will depict venom components and immunorecognition neutralization by antivenoms of Bothrops sp. endemic in French oversea areas. Second, preclinical studies in Bothrops venom–treated mice will reproduce features of pathophysiological profile observed in human, such as local edema/necrosis and systemic hemorrhage. Our study will also demonstrate for the first time that Bothrops envenoming induce inflammation through signaling pathways including TLRs and NLRP3 inflammasome activation. Third, our results will demonstrate that intravenous Bothrops venom induces mtDAMPs release, thus indicating that VAMPs may directly induce DAMPs release independently of venom-induced local injuries. Translational studies in human will show that Bothrops snake venom mixtures impair mitochondrial function and induce mtDAMPs release in ex vivo human preparations of cardiac cells and artery vessel rings. Our results will show that Bothrops toxins induce mtDNA release, mitochondrial dysfunction, abnormal vasorelaxation and endothelial cell dysfunction, which are all prevented by mitochondria-targeted antioxidants. Importantly, these results will be translated into new medical practice. Pilot clinical trials in Martinique and French Guyana will be promoted to demonstrate that elamipretide, an effective mitochondria-targeted antioxidant previously approved for clinical use, improve mitochondrial dysfunction, blunt inflammation and prevent multiple organ failure in severe Bothrops envenomation. Conclusion: Overall, our efforts will identify new pharmacological mitochondrial targets that control the inflammation process in its early stage and provide new complementary treatments to traditional antivenom immunotherapy for Bothrops envenomation.

Since 2010, massive and repeated invasions of sargassum seaweed have taken place on coasts of Caribbean countries. Stranding of brown algae represents not only an environmental and economic disaster but also a real threat to human health due to the production of toxic gaseous and organic compounds that are not yet completely all identified. Among them acute toxicity of hydrogen sulfide H2S and ammonia NH3 is well-known. In contrast, there has been no comprehensive assessment regarding potential human health hazards associated with chronic exposure to H2S. This lack of knowledge is critical because residents of hitten coasts have repeated and prolonged exposure to low concentrations of potentially toxic gases. Our clinical study performed at CHU Martinique in 2018 found that the most frequent clinical signs of chronic exposure were conjunctival and upper airway irritation, difficult breathing or shortness of breath, skin rashes and headaches. As preliminary results pointed to the respiratory system, we propose to better characterize human health consequences of gaseous emanation produced by decomposing sargassum and their association with ambient H2S and NH3 levels. Lung consequences will be assessed via spirometry and body plethysmography testing. Biomarkers of lung inflammation and oxidative stress will be measured in the exhaled air and breath condensate. Signaling pathways involved in lung toxicity will be further characterized in a mouse model. Genotoxicity and effects of prenatal exposition in mice on lung development and postnatal lung dysfunction will also be studied. Lastly, we will investigate relationships between air quality perceptions, health concerns, and social consequences based on an anthropological approach via individual observations. ). Overall, our efforts will concentrate to characterize and eventually control noxious lung impacts of sargassum thread through integrated approaches using up-to-date technologies and clinical studies.