Camponotus floridanus ants show altered behaviors followed by a fatal summiting phenotype when infected with manipulating Ophiocordyceps camponoti-floridani fungi. Host summiting as a strategy to increase transmission is also observed with parasite taxa beyond fungi, including aquatic and terrestrial helminths and baculoviruses. The drastic phenotypic changes can sometimes reflect significant molecular changes in gene expression and metabolite concentrations measured in manipulated hosts. Nevertheless, the underlying mechanisms still need to be fully characterized. To investigate the small molecules producing summiting behavior, we infected C. floridanus ants with O. camponoti-floridani and sampled their heads for LC-MS/MS when we observed the characteristic summiting phenotype. We link this metabolomic data with our previous genomic and transcriptomic data to propose mechanisms that underlie manipulated summiting behavior in "zombie ants." This "multiomic" evidence points toward the dysregulation of neurotransmitter levels and neuronal signaling. We propose that these processes are altered during infection and manipulation based on (1) differential expression of neurotransmitter synthesis and receptor genes, (2) altered abundance of metabolites and neurotransmitters (or their precursors) with known behavioral effects in ants and other insects, and (3) possible suppression of a connected immunity pathway. We additionally report signals for metabolic activity during manipulation related to primary metabolism, detoxification, and anti-stress protectants. Taken together, these findings suggest that host manipulation is likely a multi-faceted phenomenon, with key processes changing at multiple levels of molecular organization.
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