Tissue damaging toxins in snake venoms: mechanisms of action, pathophysiology and treatment strategies

Abstract

Snakebite envenoming is an important public health issue responsible for mortality and severe morbidity. Where mortality is mainly caused by venom toxins that induce cardiovascular disturbances, neurotoxicity, and acute kidney injury, morbidity is caused by toxins that directly or indirectly destroy cells and degrade the extracellular matrix. These are referred to as 'tissue-damaging toxins' and have previously been classified in various ways, most of which are based on the tissues being affected (e.g., cardiotoxins, myotoxins). This categorisation, however, is primarily phenomenological and not mechanistic. In this review, we propose an alternative way of classifying cytotoxins based on their mechanistic effects rather than using a description that is organ- or tissue-based. The mechanisms of toxin-induced tissue damage and their clinical implications are discussed. This review contributes to our understanding of fundamental biological processes associated with snakebite envenoming, which may pave the way for a knowledge-based search for novel therapeutic options.

Fig. 1. Representative venomous snakes and tissue-damaging effects associated with their envenomings.

a–c Medically important snake species with tissue-damaging properties in their venoms; (a) jararaca (Bothrops jararaca); (b) Malayan pitviper (Calloselasma rhodostoma); (c) black-necked spitting cobra (Naja nigricollis). d–f Pathologies caused by cytotoxic snake venoms; (d) swelling and blistering following a bite of B. jararaca; (e) swelling, blistering and necrosis as a result of a bite from C. rhodostoma; (f) extensive skin- and subcutaneous necrosis following a bite of N. nigricollis. Photographs of B. jararaca and C. rhodostoma courtesy of Wolfgang Wüster; the picture of N. nigricollis was taken by Johan Marais (African Snakebite Institute). Photographs of clinical cases by David A. Warrell, published in Gutiérrez et al. Nat. Rev. Dis. Primers 3: 17079.

Fig. 2. Main types of snake venom toxins and their mechanisms of action.

Some toxins have more than one biological effect, thereby creating a multi-layered image. Numbers correspond to two categories of venom-induced tissue damage: (1) direct cytotoxic effects by ‘true’ cytotoxins and (2) degradation of extracellular matrix, which may result in indirect cytotoxic effect. Toxin classes: N-3FTx: neurotoxic three-finger toxins; KUN: Kunitz-type peptides; PLA₂: phospholipase A₂s; CT-3FTxs: cytotoxic three-finger toxins; SVMP: snake venom metalloproteinases; Hyal: hyaluronidases; CTL: C-type lectins; CLP: C-type lectin-related proteins; Dis: disintegrins; SVSP: Snake venom serine proteinases. This figure was based on Ray Morgan’s ‘The Venom Interviews’, Part VII, It’s Complicated, 2016.

Fig. 3. Schematic overview representing the various mechanisms of action of tissue-damaging toxins.

(1) Direct cytotoxic effects caused by cytotoxic 3FTxs, cytotoxic PLA2s and β-defensin-like toxins. (2) Degradation of the ECM by SVMPs and hyaluronidases. Degradation of ECM contributes to the diffusion of venom components and can contribute to cellular damage indirectly by affecting the stability of endothelial cells in capillaries and by reducing blood supply as a consequence of haemorrhage, thus generating ischemia. The image was created via www.biorender.com (with permission).

Fig. 4. Overview of the tissue-damaging activities of snake venom toxins on various body systems.

Snake venoms may cause a wide range of effects in the human body and depend on the composition of the venom. The observed effects can be local and systemic. The image was created via www.biorender.com (with permission).

Fig. 5. Schematic overview representing the various mechanisms of cytotoxicity observed in vitro.

(1) Apoptosis through anoikis by SVMPs, disintegrins (and possibly C-type lectins). (2) ATP release leads to the activation of cell-death pathways and, thereby, triggering apoptosis by cytotoxic PLA₂s. (3) Apoptosis triggered by ROS production by LAAOs. (4) Activation of various cell death pathways by cytotoxic 3FTxs and cytotoxic PLA₂s. Asterisk depicts those mechanisms which are secondary to direct cytotoxicity. The image was created via www.biorender.com (with permission).