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Unravelling the mechanism of snake venom induced haemorrhage by focusing on basement membrane disruption

Grant number: 23/00670-8
Support Opportunities:Regular Research Grants
Duration: May 01, 2023 - April 30, 2025
Field of knowledge:Health Sciences - Collective Health - Public Health
Convênio/Acordo: University of Manchester
Mobility Program: SPRINT - Projetos de pesquisa - Mobilidade
Principal Investigator:Karen de Morais Zani
Grantee:Karen de Morais Zani
Principal researcher abroad: Rachel Lennon
Institution abroad: University of Manchester, England
Host Institution: Instituto Butantan. Secretaria da Saúde (São Paulo - Estado). São Paulo , SP, Brazil
Associated researchers:Anita Mitico Tanaka-Azevedo
Associated research grant:20/07268-2 - Characterization of the coagulotoxic profile of venoms of Viperidae snakes with medical importance in Brazil, AP.R

Abstract

Snakebite envenoming constitutes a highly relevant public health problem on a global scale. It primarily affects impoverished populations in the rural settings of Africa, Asia, Latin America and parts of Oceania, and is classified as a neglected tropical disease by the World Health Organization. In Brazil, the genus Bothrops is responsible for approximately 85% of the reported snakebite accidents (data recorded in 2022). Bothropic envenoming is characterized by disruption of blood coagulation and prominent local and systemic haemorrhage. Blood vessel damage leading to extravasation, in turn, contributes to local tissue damage and poor muscle regeneration, and to massive systemic blood loss leading to hemodynamic disturbances and cardiovascular shock. Venom-induced haemorrhage is the result of the action of snake venom metalloproteinases (SVMPs) in the microvasculature, especially in capillaries. It is proposed that haemorrhage occurs mostly through the SVMP-induced degradation of key structural components at the basement membrane. This enzymatic degradation causes a mechanical weakening that results in microvessel wall distention owing to the action of the hemodynamic forces operating in the circulation, with the disruption of the capillary wall and blood extravasation. The characterization of the structural and functional properties of haemorrhagic SVMPs has provided a rich body of knowledge that has expanded the understanding on the mechanism of action of these toxins in the tissues and on the structural determinants of their activity. Nevertheless, in actual snakebites, it is whole venom that is injected in the victim and, consequently, the action of toxins requires analysis in the context of venoms. Indeed, the current knowledge about haemorrhage induced by Brazilian Bothrops venoms is limited to the determination and comparison of their Minimal Hemorrhagic Dose (MHD) and to the mechanisms of action of individual toxins, besides inferences based on their relative proteomic abundance in venoms from the different species, especially regarding SVMP content and diversity. In this context, the study of how snake venoms induce haemorrhage and their mechanism of action on basement membrane components is extremely relevant within the field of Toxinology and also from a medically standpoint, due to the relevance of haemorrhagic manifestations in the overall pathophysiology of bothropic envenoming. (AU)

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