Caterpillar envenomation is a global health threat in the 21st century. Every direct or indirect contact with the urticating hairs of a caterpillar results in clinical manifestations ranging from local dermatitis symptoms to potentially life-threatening systemic effects. This is mainly due to the action of bioactive components in the venom that interfere with targets in the human body. The problem is that doctors are limited to relieve symptoms, since an effective treatment is still lacking. Only for Lonomia species an effective antivenom does exist. The health and economical damage are an underestimated problem and will be even more of a concern in the future. For some caterpillar species, the venom composition has been the subject of investigation, while for many others it remains unknown. Moreover, the targets involved in the pathophysiology are poorly understood. This review aims to give an overview of the knowledge we have today on the venom composition of different caterpillar species along with their pharmacological targets. Epidemiology, mode of action, clinical time course and treatments are also addressed. Finally, we briefly discuss the future perspectives that may open the doors for future research in the world of caterpillar toxins to find an adequate treatment.
The a-Conotoxins are peptide toxins that are found in the venom of marine cone snails and they are potent antagonists of various subtypes of nicotinic acetylcholine receptors (nAChRs). Because nAChRs have an important role in regulating transmitter release, cell excitability, and neuronal integration, nAChR dysfunctions have been implicated in a variety of severe pathologies. We describe the isolation and characterization of α-conotoxin MilIA, the first conopeptide from the venom of Conus milneedwardsi. The peptide was characterized by electrophysiological screening against several types of cloned nAChRs that were expressed in Xenopus laevis oocytes. MilIA, which is a member of the α3/5 family, is an antagonist of muscle type nAChRs with a high selectivity for muscle versus neuronal subtype nAChRs. Several analogues were designed and investigated for their activity in order to determine the key epitopes of MilIA. Native MilIA and analogues both showed activity at the fetal muscle type nAChR. Two single mutations (Met9 and Asn10) allowed for MilIA to strongly discriminate between the two types of muscle nAChRs. Moreover, one analogue, MilIA [∆1,M2R, M9G, N10K, H11K], displayed a remarkable enhanced potency when compared to native peptide. The key residues that are responsible for switching between muscle and neuronal nAChRs preference were elucidated. Interestingly, the same analogue showed a preference for α9α10 nAChRs among the neuronal types.
Over the past decades, envenomation by caterpillars of Automeris spp. became an increasing health problem in Latin America. Accidental contact with the stinging spines of these caterpillars cause acute local pain, itching, inflammation and skin rashes that persists for days. Even when the cause is obvious, the exact molecular mechanisms responsible for the observed symptoms are yet to be elucidated. Here, we describe for the first time, an active compound in the venom and the study of the bioactivity of the venom extracted from the spines of the caterpillar Automeris zaruma. Electrophysiological screening of a library of membrane proteins important for pain and itch enabled us to investigate and reveal the mode of action of the venom of A. zaruma. Further mass spectrometric analysis (Q-TOF-MS) made it possible to establish a link between the bioactivity and the components found in the venom. We show that the spine extract of A. zaruma contains histamine that potently activates the four types of the human histamine receptors (H1R, H2R, H3R and H4R) with a selectivity preference towards H3R and H4R. Furthermore, a modulation of the target MRGPRX2 was found. Together, these findings are the first to explain the symptomology of A. zaruma envenomation, enabling us a better understanding of caterpillar envenomation and predict that the hurdle of the scarce efficacy of the currently used antihistaminic drugs can be overcome by including H3R and H4R blockers in the clinical used medication. Such an approach might be used for other caterpillar envenomation in the world and represent a significant improvement for the well-being of the patient.
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