Pulmonary involvement from animal toxins: the cellular mechanisms

Abstract

Venomous animals and their venom have always been of human interest because, despite species differences, coevolution has made them capable of targeting key physiological components of our bodies. Respiratory failure from lung injury is one of the serious consequences of envenomation, and the underlying mechanisms are rarely discussed. This review aims to demonstrate how toxins affect the pulmonary system through various biological pathways. Herein, we propose the common underlying cellular mechanisms of toxin-induced lung injury: interference with normal cell function and integrity, disruption of normal vascular function, and provocation of excessive inflammation. Viperid snakebites are the leading cause of envenomation-induced lung injury, followed by other terrestrial venomous animals such as scorpions, spiders, and centipedes. Marine species, particularly jellyfish, can also inflict such injury. Common pulmonary manifestations include pulmonary edema, pulmonary hemorrhage, and exudative infiltration. Severe envenomation can result in acute respiratory distress syndrome. Pulmonary involvement suggests severe envenomation, thus recognizing these mechanisms and manifestations can aid physicians in providing appropriate treatment.

Recombinant snake antivenoms get closer to the clinic

“…Nevertheless, an unmet medical need remains because these medicines suffer from serious drawbacks relating to their nature and method of manufacture. The key drawbacks include their relatively high cost of production, limited efficacy (especially against non- or poorly immunogenic toxins), and safety concerns relating to their non-human origin which imposes a risk of causing serum sickness or even anaphylaxis in severe cases [ 3 ]. For over four decades researchers have been exploring the idea of using mAbs as a substitute for plasma-derived polyclonal antibodies of animal origin [ 2 ].…”

“…Although some work on the discovery of different mAbs was carried out in the 1980s to 2010s, none of these molecules ever entered into clinical trials, and only a few showed promising effects in neutralizing key toxins [ 2 , 3 ]. Part of the explanation is likely that all the IgG antibodies reported were of non-human (mostly murine) origin and that the human single-chain variable fragments (scFvs) discovered displayed limited therapeutic utility [ 2 , 3 ].…”

“…Although some work on the discovery of different mAbs was carried out in the 1980s to 2010s, none of these molecules ever entered into clinical trials, and only a few showed promising effects in neutralizing key toxins [ 2 , 3 ]. Part of the explanation is likely that all the IgG antibodies reported were of non-human (mostly murine) origin and that the human single-chain variable fragments (scFvs) discovered displayed limited therapeutic utility [ 2 , 3 ]. However, in 2013 the first promising camelid mAb fragment (V H H) was discovered which could protect mice against a lethal dose of α-cobratoxin from the monocled cobra [ 4 ], and in 2018 the first fully human IgG mAbs were reported that neutralized dendrotoxins from the black mamba [ 5 ].…”

“…From then it took another 4 years before a human IgG mAb could rescue mice from a lethal dose of whole venom from the monocled cobra [ 6 ], and it was not until 2023 that a human IgG mAb showed broadly neutralizing capacity against long-chain α-neurotoxins from different elapid venoms ( Figure 1 A) [ 7 ]. These discoveries were all based on phage display technology and deep insights into the composition of snake venoms [ 2 , 3 , 8 ].

Figure 1 Discovery, screening, and optimization approaches for the development of recombinant broadly neutralizing human monoclonal antibodies (mAbs) that can neutralize long-chain α-neurotoxins from elapid snakes [ 7 , 9 ].

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“…To appreciate the achievement of Khalek and colleagues, it is important to understand that snake venoms are very complex mixtures of protein-based toxins, that no two snake venoms share the same composition or even the same toxins, and that the venom of each species contains tens to hundreds of different toxins grouped into over a dozen different protein families [ 2 , 3 ]. Consequently, it is seldom sufficient to neutralize only a single specific toxin to protect a mouse or an individual against a whole venom [ 5 , 8 ].…”