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An extracellular Argonaute protein mediates export of repeat-associated small RNAs into vesicles in parasitic nematodes

ABSTRACT: Mobile small RNAs are an integral component of the arms race between plants and fungal parasites, and several studies suggest microRNAs could similarly operate between parasitic nematodes and their animal hosts. However, whether and how specific sequences are selected for export by parasites is unknown. Here we describe a specific Argonaute protein (exWAGO) that is secreted in extracellular vesicles (EVs) released by the gastrointestinal nematode Heligmosomodies bakeri, at multiple copies per EV. Phylogenetic and gene expression analyses demonstrate exWAGO is highly conserved and abundantly expressed in related parasites, including the human hookworm and proteomic analyses confirm this is the only Argonaute secreted by rodent parasites. In contrast, exWAGO orthologues in species from the free-living genus Caenorhabditis are highly diverged. By sequencing multiple small RNA libraries, we determined that the most abundant small RNAs released from the nematode parasite are not microRNAs but rather secondary small interfering RNAs (siRNAs) that are produced by RNA-dependent RNA Polymerases. We further identify distinct evolutionary properties of the siRNAs resident in free-living or parasitic nematodes versus those exported in EVs by the parasite and show that the latter are specifically associated with exWAGO. Together this work identifies an Argonaute protein as a mediator of RNA export and suggests rhabditomorph nematode parasites may have co-opted a novel nematode-unique pathway to communicate with their hosts.

ORGANISM(S): Caenorhabditis elegans Heligmosomoides bakeri

PROVIDER: GSE117169 | GEO | 2019/02/21

REPOSITORIES: GEO

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Project description:Infections and diseases caused by parasitic nematodes have a major adverse impact on the health and productivity of animals and humans worldwide. The control of these parasites often relies heavily on the treatment with commercially available chemical compounds (anthelmintics). However, the excessive or uncontrolled use of these compounds in livestock animals has led to major challenges linked to drug resistance in nematodes. Therefore, there is a need to develop new anthelmintics with novel mechanism(s) of action. Recently, we identified a small molecule, KM08948, with nematocidal activity against the free-living model organism Caenorhabditis elegans. Here, we evaluated KM08948’s potential as an anthelmintic in a structure-activity relationship (SAR) study in C. elegans and in the highly pathogenic, blood-feeding Haemonchus contortus (barber’s pole worm), and explored the compound-target relationship using thermal proteome profiling (TPP). First, we synthesised and tested a series of 25 KM08948 analogues for nematocidal activity in both H. contortus (larvae and adults) and C. elegans (young adults), establishing a preliminary nematocidal pharmacophore for both species. We identified several compounds with marked activity against either H. contortus or C. elegans which had greater efficacy than KM08948, and found a significant divergence in compound bioactivity between these two nematode species. We also identified a KM08948 analogue, 25, that moderately inhibited the motility of adult female H. contortus in vitro. Subsequently, we inferred three H. contortus proteins (HCON_00134350, HCON_00021470 and HCON_00099760) and five C. elegans proteins (F30A10.9, F15B9.8, B0361.6, DNC-4 and UNC-11) that interacted directly with KM08948; however, no conserved protein target was shared between the two nematode species. Future work aims to extend the SAR investigation in these and other parasitic nematode species, and validate individual proteins identified here as targets of KM08948. Overall, the present study describes an evaluation of this anthelmintic candidate and highlights some challenges associated with early anthelmintic discovery.

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An extracellular Argonaute protein mediates export of repeat-associated small RNAs into vesicles in parasitic nematodes

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