Unraveling the venom chemistry with evidence for histamine as key regulator in the envenomation by caterpillar Automeris zaruma

Abstract

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.

Modulation of the Mas-Related G Protein-Coupled Receptor X2 (MRGPRX2) by Xenobiotic Compounds and Its Relevance to Human Diseases

“…Exogenous ligands of MRGPRX2 include the cationic polymer compound 48/80 (C48/80), which is commonly used in receptor functional assays, and a variety of drugs approved by the Food and Drug Administration (FDA), such as fluoroquinolones (e.g., ciprofloxacin), neuromuscular blocking agents (e.g., rocuronium, atracurium), opioids (e.g., morphine), and many others [ 4 , 9 , 28 ]. MRGPRX2 can also be activated or inhibited by other exogenous agents, such as bacterial quorum sensing proteins, insect venoms [ 3 , 29 , 30 ], or many different plant xenobiotics ( Figure 1 ) [ 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 ]; representatives of which are described in the following part of this review.…”

Histamine excretion in common indoor and hematophagous arthropods

“…Histamine has also been found in the excreta of another Hemipteran, Rhodnius prolixus (Stål) (Hemiptera: Reduviidae) (Harington 1956), but it is unclear if histamine serves as an arrestant like in bed bugs, or if histamine in the feces has other roles. Histamine has also been found in insect venom, including that from some species of stinging caterpillars, likely exacerbating allergic reactions (Karlsson and Einarsson 1982, Seldeslachts et al 2022).…”

Histamine Receptors: Ex Vivo Functional Studies Enabling the Discovery of Hits and Pathways

“…These receptors belong to the aminergic clade of class A (rhodopsin-like) GPCRs and exhibit a shared structural feature, encompassing an extracellular N-terminus, seven transmembrane helices, three extracellular loops, three intracellular loops, and an intracellular C-terminus (Figure 1) [3]. H1R-H4R are widely distributed in the body and have been at the center of attention due to their role in allergic reactions, inflammation, gastric acid regulation, neurotransmission, immune modulation, and envenomation by venomous animals [4,5].…”