Investigating Snake-Venom-Induced Dermonecrosis and Inflammation Using an Ex Vivo Human Skin Model

Author:

Alsolaiss Jaffer12ORCID,Leeming Gail3,Da Silva Rachael1,Alomran Nessrin14,Casewell Nicholas R.1ORCID,Habib Abdulrazaq G.5,Harrison Robert A.1,Modahl Cassandra M.1ORCID

Affiliation:

1. Centre for Snakebite Research and Interventions, Liverpool School of Tropical Medicine, Liverpool L3 5QA, UK

2. Abqaiq General Hospital, Rural Health Network, Eastern Health Cluster, Ministry of Health, Abqaiq 33241, Saudi Arabia

3. Department of Veterinary Anatomy, Physiology and Pathology, School of Veterinary Science, University of Liverpool, Liverpool L69 7ZX, UK

4. Qatif Medical Fitness Center, Clinical Laboratory Department, Qatif Health Network, Eastern Health Cluster, Ministry of Health, Qatif 31911, Saudi Arabia

5. African Snakebite Research Group (ASRG) Project, Bayero University, Kano 700251, Nigeria

Abstract

Snakebite envenoming is a neglected tropical disease that causes >100,000 deaths and >400,000 cases of morbidity annually. Despite the use of mouse models, severe local envenoming, defined by morbidity-causing local tissue necrosis, remains poorly understood, and human-tissue responses are ill-defined. Here, for the first time, an ex vivo, non-perfused human skin model was used to investigate temporal histopathological and immunological changes following subcutaneous injections of venoms from medically important African vipers (Echis ocellatus and Bitis arietans) and cobras (Naja nigricollis and N. haje). Histological analysis of venom-injected ex vivo human skin biopsies revealed morphological changes in the epidermis (ballooning degeneration, erosion, and ulceration) comparable to clinical signs of local envenoming. Immunostaining of these biopsies confirmed cell apoptosis consistent with the onset of necrosis. RNA sequencing, multiplex bead arrays, and ELISAs demonstrated that venom-injected human skin biopsies exhibited higher rates of transcription and expression of chemokines (CXCL5, MIP1-ALPHA, RANTES, MCP-1, and MIG), cytokines (IL-1β, IL-1RA, G-CSF/CSF-3, and GM-CSF), and growth factors (VEGF-A, FGF, and HGF) in comparison to non-injected biopsies. To investigate the efficacy of antivenom, SAIMR Echis monovalent or SAIMR polyvalent antivenom was injected one hour following E. ocellatus or N. nigricollis venom treatment, respectively, and although antivenom did not prevent venom-induced dermal tissue damage, it did reduce all pro-inflammatory chemokines, cytokines, and growth factors to normal levels after 48 h. This ex vivo skin model could be useful for studies evaluating the progression of local envenoming and the efficacy of snakebite treatments.

Funder

Saudi Cultural Bureau

Wellcome Trust snakebite

AMS Springboard

Publisher

MDPI AG

Reference85 articles.

1. WHO (2022, July 19). Neglected Tropical Diseases. Available online: http://www.who.int/neglected_diseases/diseases/en/.

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4. The Clinical Management of Snake Bites in the Southeast Asian Region;Warrell;Southeast Asian J. Trop. Med. Public Helath,1999

5. WHO (2010). Guidelines for the Prevention and Clinical Management of Snakebite in Africa, WHO Regional Office for Africa.

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