An Argonaute protein traffics from nematode to mouse and is a vaccine against parasitic nematodes
Argonautes are ancient proteins with well-characterised functions in cell-autonomous gene regulation and genome defence, but less clear roles in non-cell-autonomous processes. Extracellular Argonautes have been reported across plants, animals and protozoa, yet their biochemical and functional properties remain elusive. Here, we demonstrate that an extracellular Argonaute (exWAGO) released by the rodent-infective nematode Heligmosomoides bakeri is detectable inside mouse cells during the natural infection. We show that exWAGO is released from H. bakeri in both vesicular and non-vesicular forms that have different resistances to proteolysis, different accessibilities to antibodies and associate with different subsets of secondary siRNAs. Using recombinant exWAGO protein, we demonstrate that non-vesicular exWAGO is internalised by mouse cells in vitro and that immunisation of mice with exWAGO confers partial protection against subsequent H. bakeri infection and generates antibodies that block exWAGO uptake into cells. Finally, we show that properties of exWAGO are conserved across Clade V nematodes that infect humans and livestock. Together, this work expands the context in which Argonautes function and illuminates an RNA-binding protein as a vaccine target for parasitic nematodes.
Authors
- Hanchen Li (ORCID: https://orcid.org/0009-0005-9980-028X)
- V Jayaraman (ORCID: https://orcid.org/0009-0005-4968-5017)
- Rick M. Maizels (ORCID: https://orcid.org/0000-0003-3216-1944)
- Cei Abreu‐Goodger (ORCID: https://orcid.org/0000-0001-8302-9893)
- Isaac Martínez-Ugalde (ORCID: https://orcid.org/0000-0001-7866-3216)
- Raffi V. Aroian (ORCID: https://orcid.org/0000-0002-9741-3834)
- David J. Wright (ORCID: https://orcid.org/0000-0001-8666-4155)
- Thomas M. Fenton (ORCID: https://orcid.org/0000-0002-6200-6403)
- Amy H. Buck (ORCID: https://orcid.org/0000-0003-2645-7191)
- José Roberto Bermúdez‐Barrientos (ORCID: https://orcid.org/0000-0002-4855-4016)
- Kyriaki Neophytou (ORCID: https://orcid.org/0000-0003-4311-9776)
- Yvonne Harcus
- Alasdair J. Nisbet (ORCID: https://orcid.org/0000-0002-4965-5396)
- E. Douglas Robertson (ORCID: https://orcid.org/0009-0006-2478-0920)
- Mike Evans (ORCID: https://orcid.org/0000-0002-2332-4425)
- Ruby White (ORCID: https://orcid.org/0000-0002-2503-9169)
- Chanel M. Naar (ORCID: https://orcid.org/0000-0003-3054-7472)
- Daniel R. G. Price (ORCID: https://orcid.org/0000-0002-4819-0654)
- Lewis J. Strachan (ORCID: https://orcid.org/0009-0004-9668-292X)
Institutions
- University of Massachusetts Chan Medical School (US)
- University of Toronto (CA)
- University of Cambridge (GB)
- Leiden University Medical Center (NL)
- Cancer Research UK (GB)
- Moredun Research Institute (GB)
- Cancer Research UK Scotland Institute (GB)
- University of Glasgow (GB)
- University of Edinburgh (GB)
Publication Details
- Journal
- EMBO Reports
- Published
- 2025-12-09
- DOI
- https://doi.org/10.1038/s44319-025-00620-4
- Citations
- 2
- Primary Topic
- Parasites and Host Interactions
- Type
- article
- Field-Weighted Citation Impact
- 4.10
Funders
- Wellcome Trust
- Rural and Environment Science and Analytical Services Division
- University of Edinburgh
- Consejo Nacional de Ciencia y Tecnología
- Darwin Trust of Edinburgh
- National Institutes of Health