CE17 - Recherche translationnelle en santé

BOTHROPS SNAKE ENVENOMATION ENGAGES ABERRANT HOST DEFENSE RESPONSE THROUGH RECOGNITION OF CELLULAR AND MITOCHONDRIAL DAMAGE-ASSOCIATED MOLECULAR PATTERNS (DAMPS) TO INDUCE MULTIPLE ORGAN AND DEATH – MITOBOTHROPS

Submission summary

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.

Project coordination

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

Partner

INSERM U1144 VARIABILITE DE LA REPONSE AUX PSYCHOTROPES (VARIAPSY)
Universidad de Costa Rica / Instituto Clodomiro Picado, Facultad de Microbiología
UMR 216 MERIT UMR 216 MÈRE ET ENFANT FACE AUX INFECTIONS TROPICALES
CHUM Centre Hospitalier Universitaire de Martinique
CHU Martinique CHU Martinique

Help of the ANR 516,215 euros
Beginning and duration of the scientific project: December 2018 - 36 Months

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