Experimental vaccine targeting a worm secreted Argonaute protein cuts parasitic infection in mice

Gene regulation is tightly controlled by Argonaute proteins and small RNAs inside cells. These proteins act as the key effectors of RNA silencing, which is a fundamental gene regulatory mechanism.

Although Argonautes have been discovered outside of cells in plants and animals, the function of extracellular Argonautes is unknown.

In this study researchers demonstrate that a gastrointestinal nematode (Heligmosomoides bakeri) that infects mice secretes an extracellular Argonaute protein known as 'exWAGO', bound to small RNAs that can enter host cells.

When researchers vaccinated mice with a lab‑made version of exWAGO, the mice ended up with fewer worms. This points to a new vaccine approach against parasitic worms, which remain a major global health problem.

Intestinal worms infect around one in four people worldwide. Researchers use H. bakeri, a worm that naturally infects mice, to understand how these infections work and how to stop them.

Worms release a mix of substances into their surroundings inside the host. This mix is called excretory–secretory (ES) products and includes proteins and RNA molecules, as well as tiny packages called extracellular vesicles, or EVs, which also carry proteins and RNA.

Inside cells, many organisms use small RNA molecules, called siRNAs, together with helper proteins called Argonautes, to turn off specific genes. Nematode worms have developed an additional family of Argonautes known as WAGOs (worm-specific Argonautes). Researchers had previously found that a particular WAGO protein from H. bakeri, named Hb‑exWAGO, appears inside and outside the worm’s EVs along with siRNAs.

Researchers used vaccination to target the version of Hb‑exWAGO that is exposed to the host environment during infection outside EVs. They made a recombinant, or lab‑produced, Hb‑exWAGO protein and vaccinated mice with it before infecting them with the worm.

They tested whether antibodies made during infection could stop Hb‑exWAGO, when it is not inside vesicles, from entering cells.

They also used tissue staining methods to look for Hb‑exWAGO moving from the worm into mouse cells during normal infection. 

Researchers found that vaccination with exWAGO confers partial protection against subsequent worm infection and generates antibodies that block exWAGO internalisation by mouse host cells.

Antibodies generated during infection blocked the entry of Hb‑exWAGO into cells when the protein was in a non‑vesicular form. Tissue staining showed that Hb‑exWAGO moves from the nematode into mouse cells during natural infection.

Similar proteins in related parasitic nematodes showed the same key traits: strong production in adult worms, release in ES products, and a preference for binding to “secondary” siRNAs that amplify gene‑silencing signals

These results provide a functional look at an Argonaute protein that operates outside cells during infection in a living host.

The results identify Hb‑exWAGO as a promising vaccine target which is important because there are currently no vaccines for human worm infections, only limited options for animals, and growing resistance to anti‑worm drugs.

A key next step for this research is also to interrogate how exWAGO and its associated small RNAs might be involved in silencing of host genes.

School of Biological Sciences

Buck Lab