Abstract
Snakebite is a major neglected tropical health issue that affects over 5 million people worldwide resulting in around 1.8 million envenomations and 100,000 deaths each year. Snakebite envenomation also causes innumerable morbidities, specifically loss of limbs as a result of excessive tissue/muscle damage. Snake venom metalloproteases (SVMPs) are a predominant component of viper venoms, and are involved in the degradation of basement membrane proteins (particularly collagen) surrounding the tissues around the bite site. Although their collagenolytic properties have been established, the molecular mechanisms through which SVMPs induce permanent muscle damage are poorly understood. Here, we demonstrate the purification and characterisation of an SVMP from a viper (Crotalus atrox) venom. Mass spectrometry analysis confirmed that this protein is most likely to be a group III metalloprotease (showing high similarity to VAP2A) and has been referred to as CAMP (Crotalus atrox metalloprotease). CAMP displays both collagenolytic and fibrinogenolytic activities and inhibits CRP-XL-induced platelet aggregation. To determine its effects on muscle damage, CAMP was administered into the tibialis anterior muscle of mice and its actions were compared with cardiotoxin I (a three-finger toxin) from an elapid snake (Naja pallida) venom. Extensive immunohistochemistry analyses revealed that CAMP significantly damages skeletal muscles by attacking the collagen scaffold and other important basement membrane proteins, and prevents their regeneration through disrupting the functions of satellite cells. In contrast, cardiotoxin I destroys skeletal muscle by damaging the plasma membrane, but does not impact regeneration due to its inability to affect the extracellular matrix. Overall, this study provides novel insights into the mechanisms through which SVMPs induce permanent muscle damage.
Highlights
Snakebite envenomation is a recently reinstated neglected tropical disease [1] that causes around 100,000 deaths annually [2, 3] and innumerable permanent disabilities predominantly on the rural population living in the lower income regions of the world [4,5,6]
To determine the actions of CAMP in the development of permanent muscle damage, it was injected into the muscle of mice in a parallel comparison with cardiotoxin I
The results demonstrate that through a combination of effects on the structural scaffolds surrounding the tissues, blood vessels and regeneration, CAMP significantly affects the muscles, thereby leading to permanent muscle damage
Summary
Snakebite envenomation is a recently reinstated neglected tropical disease [1] that causes around 100,000 deaths annually [2, 3] and innumerable permanent disabilities predominantly on the rural population living in the lower income regions of the world [4,5,6]. Snake venom metalloproteases (SVMPs) primarily induce local envenomation effects such as swelling, necrosis and extensive tissue/muscle damage as well as the activation of certain coagulation factors and degradation of fibrinogen. Extensive tissue damage is frequently treated by fasciotomy, a surgical procedure to remove the damaged tissues, cleaning the affected areas followed by skin graft or amputation of affected limbs or fingers when fasciotomy fails to suffice [7]. This results in permanent disabilities for victims, and significantly affects their socio-economic status following snakebites. Long term (persisting for over 13 years) musculoskeletal disabilities were found in over 3% of snakebite victims in a rural population of Sri Lanka and of these over 15% had to undergo amputations [17]
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