Octopamine signaling in the metazoan pathogen S chistosoma mansoni: localization, small-molecule screening and opportunities for drug development

Abstract

Schistosomiasis is a tropical disease caused by a flatworm trematode parasite that infects over 200 million people worldwide. Treatment and control of the disease rely on just one drug, praziquantel. The possibility of drug resistance coupled with praziquantel's variable efficacy encourages the identification of new drugs and drug targets. Disruption of neuromuscular homeostasis in parasitic worms is a validated strategy for drug development. In schistosomes, however, much remains to be understood about the organization of the nervous system, its component neurotransmitters and potential for drug discovery. Using synapsin as a neuronal marker, we map the central and peripheral nervous systems in the Schistosoma mansoni adult and schistosomulum (post-infective larva). We discover the widespread presence of octopamine (OA), a tyrosine-derived and invertebrate-specific neurotransmitter involved in neuromuscular coordination. OA labeling facilitated the discovery of two pairs of ganglia in the brain of the adult schistosome, rather than the one pair thus far reported for this and other trematodes. In quantitative phenotypic assays, OA and the structurally related tyrosine-derived phenolamine and catecholamine neurotransmitters differentially modulated schistosomulum motility and length. Similarly, from a screen of 28 drug agonists and antagonists of tyrosine-derivative signaling, certain drugs that act on OA and dopamine receptors induced robust and sometimes complex concentration-dependent effects on schistosome motility and length; in some cases, these effects occurred at concentrations achievable in vivo. The present data advance our knowledge of the organization of the nervous system in this globally important pathogen and identify a number of drugs that interfere with tyrosine-derivative signaling, one or more of which might provide the basis for a new chemotherapeutic approach to treat schistosomiasis..

Schistosomiasis Drug Discovery in the Era of Automation and Artificial Intelligence

“…The subtracted pixels represent a change in parasite position over time and are used as a metric to measure worm´motility (66). These methods were employed to evaluate the effect of different compounds on schistosome NTS/adults worms, such as tyrosinederived signaling agonists/antagonists (74), natural alkaloids (75)(76)(77) and analogs (77,78), as well as others with biological activity in humans (e.g., NPS-2143, a calcium-sensing receptor antagonist) (77).…”

Quantifying the mechanics of locomotion of the schistosome pathogen with respect to changes in its physical environment

“…Mechanically, this 'blended' locomotion mode is efficient because (i) it allows the suckers to contribute to locomotion in a restrictive physical environment while still exerting low traction stresses, (ii) it abolishes the resistance force created by the otherwise passive head region of the worm and (iii) the synchronous succession of head extension and firing of peristaltic waves leads to an increased stride length ( figure 11b). Our recent studies reveal that S. mansoni has a unique brain among flatworms that comprises two pairs of cerebral ganglia, one pair forward of the ventral sucker and the other aft of the oral sucker [5]. These data pose a fundamental question for brain function involved in controlling the performance of and interplay between body wave-and sucker-based locomotion.…”

“…Schistosomes possess a muscular system made up of circular, oblique and longitudinal muscles intricately interlaced with a nervous system that uses both classical and peptidergic signalling [4][5][6]. This neuromuscular complexity results in remarkable plasticity in parasite shape and movement [7,8].…”

Quantifying the mechanics of locomotion of the schistosome pathogen with respect to changes in its physical environment

“…Mechanically, this "blended" locomotion mode is efficient because 1) it allows the suckers to contribute to locomotion in a restrictive physical environment while still exerting low traction stresses, 2) it abolishes the resistance force created by the otherwise passive head region of the worm, and 3) the synchronous succession of head extension and firing of peristaltic waves leads to an increased stride length ( Figure 11B). Our recent studies reveal that S. mansoni has a unique brain among flatworms that comprises two pairs of cerebral ganglia, one pair forward of the ventral sucker and the other aft of the oral sucker (5). These data pose a fundamental question for brain function involved in controlling the performance of and interplay between body wave-and sucker-based locomotion.…”

“…Schistosomes possess a muscular system made up of circular, oblique and longitudinal muscles intricately interlaced with a nervous system that utilizes both classical and peptidergic signaling (4)(5)(6). This neuromuscular complexity results in a remarkable plasticity in parasite shape and movement (7,8).…”