ABOVE: The venom of Australian giant red bull ants (Myrmecia gulosa) contains a peptide that triggers hypersensitivity to pain in echidnas, one of the ant’s primary predators. SAM ROBINSON

EDITOR’S CHOICE IN BIOCHEMISTRY

When University of Queensland molecular biologist Sam Robinson first broke down the venom of Australian giant red bull ants (Myrmecia gulosa), he was looking for compounds that might be used in chronic pain therapies for humans. Scientists knew at the time that bull ant bites “hurt a lot,” says Robinson, but they didn’t know why. He suspected something in the venom was exacerbating the pain—something that might, paradoxically, reveal new targets for treatments. 

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Using liquid chromatography to identify the venom components, Robinson and his colleagues found that to deter predators, these ants have evolved to exploit existing pain pathways in mammals, particularly in echidnas (Tachyglossus aculeatus), which dig up their nests. In addition to common peptides similar to those found in bees, the ants’ venom contained a novel molecule that stood out. The peptide, called MIITX2-Mg1a, closely resembled echidna vertebrate hormones called epithelial growth factors (EGFs)—a previously undocumented example of molecular mimicry. 

Testing the venom cocktail in mammalian cells and mice, the researchers found that it delivered a one-two punch: the traditional venom peptides hit first, while the EGF mimic bound to the EGF receptor and triggered ongoing hypersensitivity that, in mice, made the next bite more painful. “If these echidnas are raiding these ants’ nests, that’s a huge selective pressure, and I’m not surprised that the ants try to target that particular predator,” says Adria LeBoeuf, a biologist at the University of Fribourg in Switzerland who didn’t work on the study.

Robinson notes that his team didn’t find the EGF-mimicking peptides in other ant species. But because EGF receptors are ubiquitous in mammals, he adds, the study represents a “strong line of evidence” for the emerging hypothesis that these receptors play an important role in chronic pain, and that pharmacologically blocking them could prove therapeutic.

D.A. Eagles et al., “A peptide toxin in ant venom mimics vertebrate EGF-like hormones to cause long-lasting hypersensitivity in mammals,” PNAS, 119:e2112630119, 2022.