Characterisation of venom-induced dermonecrosis, inflammatory responses and identification of causal toxins in three medically relevant African snake venoms

Bartlett, Keirah (2024) Characterisation of venom-induced dermonecrosis, inflammatory responses and identification of causal toxins in three medically relevant African snake venoms, Thesis (Doctoral), Liverpool School of Tropical Medicine.

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Abstract

Snakebite envenoming is a neglected tropical disease, primarily affecting resource-constrained communities of the tropics, leading to as many as five million bites each year. Localised tissue damage around the bite site is of particular importance, as current antivenom therapies are not effective in combatting this pathology. Understanding the progression of local pathology caused by key medically important snakes is crucial to improving clinical outcomes for affected patients. This thesis investigated the venoms of three medically important African species: Naja nigricollis (spitting cobra), Echis romani (saw-scaled viper), and Bitis arietans (puff adder).

To characterise differences in venom cytotoxicity from these three species, we first utilised a preclinical murine model of envenoming. Intradermal (ID) dosing of these venoms, with mice euthanised at time points up to 72 h post-injection, provided a time course of pathology development. Resulting dermonecrotic lesions showed N. nigricollis venom gradually increased lesion size and severity over time, with small lesions developing early in the time course around 3h. Comparatively, envenoming by both E. romani and B. arietans was characterised by intense lesions and local haemorrhaging from 3 h post-envenoming.

Next, we investigated which toxins in these venoms contributed to local tissue damage. Our cell-based assays showed N. nigricollis cytotoxic three-finger toxins (CTx) were primarily responsible for cytotoxicity. Comparatively, the ID murine model with mice culled at 72 h showed that a combination of CTx and phospholipases A2 was essential for causing dermonecrosis in vivo. Investigating E. romani and B. arietans venoms, using a combination of cell-based assays, SDS-PAGE, and snake venom metalloproteinase (SVMP) activity assays, showed that SVMP toxins in E. romani and B. arietans venoms were responsible for in vitro cytotoxicity. Finally, we investigated whether host inflammatory responses following envenoming contributed to local pathology. Using the murine model, mice were ID injected with venom followed by combinations of antivenom or anti-inflammatory drugs (dexamethasone or diclofenac). Analysis confirmed inflammation contributed to the development of dermonecrosis for all three venoms.

Understanding the development and progression of dermonecrosis provides valuable insight into how these venoms work and potential avenues to counteract the toxins responsible for this pathology. In addition to characterising this pathology for three medically relevant African snakes, we identified their predominant cytotoxic toxins. The inflammatory response in mice to these venoms furthered lesion development, suggesting anti-inflammatory drugs may provide additional clinical benefit for snakebite patients as an adjunct therapy, in addition to conventional antivenom treatment.

Item Type:	Thesis (Doctoral)
Subjects:	QW Microbiology and Immunology > Antigens and Antibodies. Toxins and Antitoxins > QW 630 Toxins. Antitoxins WD Disorders of Systemic, Metabolic or Environmental Origin, etc > Animal Poisons > WD 410 Reptiles
Faculty: Department:	Biological Sciences > Department of Tropical Disease Biology
Depositing User:	Lynn Roberts-Maloney
Date Deposited:	04 Dec 2024 11:58
Last Modified:	04 Dec 2024 12:01
URI:	https://archive.lstmed.ac.uk/id/eprint/25725

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