Naja annulifera Snake: New insights into the venom components and pathogenesis of envenomation

Abstract

BackgroundNaja annulifera is a medically important venomous snake occurring in some of the countries in Sub-Saharan Africa. Accidental bites result in severe coagulation disturbances, systemic inflammation and heart damage, as reported in dogs, and death, by respiratory arrest, in humans. Despite the medical importance of N. annulifera, little is known about its venom composition and the pathogenesis of envenomation. In this paper, the toxic, inflammatory and immunogenic properties of N. annulifera venom were analyzed.Methodology/Principal findingsVenom proteomic analysis identified 79 different proteins, including Three Finger Toxins, Cysteine Rich Secretory Proteins, Metalloproteinases, Phospholipases A2 (PLA2), Hyaluronidase, L-amino-acid oxidase, Cobra Venom Factor and Serine Proteinase. The presence of PLA2, hyaluronidase, fibrinogenolytic and anticoagulant activities was detected using functional assays. The venom was cytotoxic to human keratinocytes. In an experimental murine model of envenomation, it was found that the venom induced local changes, such as swelling, which was controlled by anti-inflammatory drugs. Moreover, the venom caused death, which was preceded by systemic inflammation and pulmonary hemorrhage. The venom was shown to be immunogenic, inducing a strong humoral immune response, with the production of antibodies able to recognize venom components with high molecular weight and to neutralize its lethal activity.Conclusions/SignificanceThe results obtained in this study demonstrate that N. annulifera venom contains toxins able to induce local and systemic inflammation, which can contribute to lung damage and death. Moreover, the venom is immunogenic, an important feature that must be considered during the production of a therapeutic anti-N. annulifera antivenom.

Amplification of Snake Venom Toxicity by Endogenous Signaling Pathways

“…A similar pattern of injury mediated by PLA 2 in muscle tissue has been described [16]. Mediation of inflammatory pathways by metalloproteases is also likely to contribute to these effects [90].…”

“…In mice, 2LD 50 dose of Naja venom caused both neutrophilia and monocytosis. In an in vivo experimental model in mice, Silva-de-Franca et al [90] found that Naja annulifera venom induced swelling and several histopathologic changes in the hind paws of the animals. In addition, myonecrosis associated with inflammation was observed, an event that is commonly found in experimental models of elapid envenoming.…”

“…Venoms, through their PLA 2 activity, achieve potent, multi-site anticoagulation by co-opting just a few key processes that regulate coagulation. Accordingly, venom PLA 2 is a prime target for therapeutic intervention in the coagulopathy of snakebite [2,8,90,102].…”

Bitis arietans Snake Venom Induces an Inflammatory Response Which Is Partially Dependent on Lipid Mediators

“…Cytokines, including IL-6, TNF-α and IL-1β, and chemokines, such as CCL-2, also known as MCP-1 also have their production increased [14][15][16][17]. These venoms also trigger the release of lipid mediators derived from membrane phospholipids, such as platelet-activating factor (PAF), and arachidonic acid (AA)-derived eicosanoids produced by cyclooxygenases 1/2 (COX1/2), such as prostaglandins (PGs) and thromboxane (TXs), and by 5-lipoxygenase (5-LO), giving rise to leukotrienes (LTs) [14,[17][18][19]. These lipid mediators, which are produced by resident and inflammatory cells, are involved in several steps of the inflammatory response, including the development of pain, edema, chemotaxis and leukocyte activation, besides the resolution phase [20].…”

Propriedades inflamatórias do veneno da serpente >i<Bitis arietans>/i<: contribuição dos mediadores lipídicos no envenenamento >i<in vivo>/i< e ação de toxinas isoladas do veneno em macrófagos humanos

“…Diversos estudos mostraram que a inflamação induzida por venenos é parcialmente dependente de mediadores lipídicos,212,229,234 o que nos levou a avaliar a contribuição destes mediadores para os eventos agudos provocados pelo veneno de B. arietans. Neste sentido, o primeiro passo foi avaliar a contribuição destes mediadores para o aumento da permeabilidade vascular.…”