The Deadly Toxin Arsenal of the Tree-Dwelling Australian Funnel-Web Spiders.

Australian funnel-web spiders are amongst the most dangerous venomous animals. Their venoms induce potentially deadly symptoms, including hyper- and hypotension, tachycardia, bradycardia and pulmonary oedema. Human envenomation is more frequent with the ground-dwelling species, including the infamous Sydney funnel-web spider (); although, only two tree-dwelling species induce more severe envenomation. To unravel the mechanisms that lead to this stark difference in clinical outcomes, we investigated the venom transcriptome and proteome of arboreal and . Overall, venoms comprised 44 toxin superfamilies, with 12 being exclusive to tree-dwellers. Surprisingly, the major venom components were neprilysins and uncharacterized peptides, in addition to the well-known ω- and δ-hexatoxins and double-knot peptides. The insecticidal effects of venom on sheep blowflies were more potent than venom, and the venom of both tree- and ground-dwelling species potently modulated human voltage-gated sodium channels, particularly Na1.2. Only the venom of tree-dwellers exhibited potent modulation of voltage-gated calcium channels. appeared to be under less diversifying selection pressure compared to the newly adapted tree-dweller, . Thus, this study contributes to unravelling the fascinating molecular and pharmacological basis for the severe envenomation caused by the Australian tree-dwelling funnel-web spiders.