Beckeson, W. C.; Werner, S.; Goebbels, M.; Ramalho, J. J.; Swafford, A.; Soroka, I.; Wingert, S. T.; Boxem, M.; Ruijtenberg, S.; Stephens, G. J.; van den Heuvel, S.; de Bekker, C.

Parasite-adaptive manipulation of behavior is a widespread natural phenomenon. While Ophiocordyceps zombie fungi are well-known for hijacking ant behavior to increase their fitness, functionally characterizing the biomolecules involved in behavior manipulation remains difficult in these non-model organisms. To circumvent this problem, we have adopted the powerful genetics toolbox of Caenorhabditis elegans to identify molecular targets and neurophysiological effects of candidate Ophiocordyceps effectors. With this approach, we discovered a novel cysteine-rich, small secreted fungal peptide that binds to well-conserved calcium-dependent scramblase channels in neurons, particularly those associated with sensory tissues. This binding suppressed nematode motor coordination and dampened ant olfactory systems vital for communication. Our findings are the thus first to directly connect an Ophiocordyceps effector with its extended phenotype, demonstrating the neuroethological role of Scramblase-1.