Date Published: October 9, 2015
Publisher: Public Library of Science
Author(s): Si-Ming Zhang, Sarah K. Buddenborg, Coen M. Adema, John T. Sullivan, Eric S. Loker, Matty Knight. http://doi.org/10.1371/journal.pntd.0004131
Abstract: In view of the call by the World Health Organization (WHO) for elimination of schistosomiasis as a public health problem by 2025, use of molluscicides in snail control to supplement chemotherapy–based control efforts is likely to increase in the coming years. The mechanisms of action of niclosamide, the active ingredient in the most widely used molluscicides, remain largely unknown. A better understanding of its toxicology at the molecular level will both improve our knowledge of snail biology and may offer valuable insights into the development of better chemical control methods for snails. We used a recently developed Biomphalaria glabrata oligonucleotide microarray (31K features) to investigate the effect of sublethal exposure to niclosamide on the transcriptional responses of the snail B. glabrata relative to untreated snails. Most of the genes highly upregulated following exposure of snails to niclosamide are involved in biotransformation of xenobiotics, including genes encoding cytochrome P450s (CYP), glutathione S-transferases (GST), and drug transporters, notably multi-drug resistance protein (efflux transporter) and solute linked carrier (influx transporter). Niclosamide also induced stress responses. Specifically, six heat shock protein (HSP) genes from three super-families (HSP20, HSP40 and HSP70) were upregulated. Genes encoding ADP-ribosylation factor (ARF), cAMP response element-binding protein (CREB) and coatomer, all of which are involved in vesicle trafficking in the Golgi of mammalian cells, were also upregulated. Lastly, a hemoglobin gene was downregulated, suggesting niclosamide may affect oxygen transport. Our results show that snails mount substantial responses to sublethal concentrations of niclosamide, at least some of which appear to be protective. The topic of how niclosamide’s lethality at higher concentrations is determined requires further study. Given that niclosamide has also been used as an anthelmintic drug for decades and has been found to have activity against several types of cancer, our findings may be of relevance in understanding how both parasites and neoplastic cells respond to this compound.
Partial Text: Schistosomiasis, caused by blood-dwelling digenetic trematodes of the genus Schistosoma, is one of the world’s major neglected tropical diseases. By conservative estimates, at least 230 million people worldwide are infected with Schistosoma spp. . Among eukaryotic parasites, the global health impact of schistosomiasis is second only to malaria.
The primary objective of the study was to use microarray analysis to reveal differential gene expression in response to 24-hr exposure to three sublethal concentrations of niclosamide. The highest concentration (0.15 mg/L) resulted in 21% mortality whereas the two lower concentrations (0.10 mg/L and 0.05 mg/L) did not cause any mortality. These results agreed with mortality data reported previously [37,38].
This study interrogated the most comprehensive B. glabrata microarray currently available, one that includes enough features to provide a representative overview of the transcripts this snail is capable of producing, including those in response to molluscicides. As such, the array (and the results derived from its use) will provide an appropriate tool to help validate, and provide perspective for next-gen sequencing studies of the responses of B. glabrata and other schistosome-transmitting snails to molluscicides. Furthermore, unlike next-gen sequencing approaches, microarrays do not require application of assembly software that can introduce errors and produce artifactual chimeric sequences. As the use of molluscicides will increase in the near future, having as many sources of information as possible about their impact on snail biology will be beneficial.