Extracellular Vesicles from a Helminth Parasite Suppress Macrophage Activation and Constitute an Effective Vaccine for Protective Immunity

Abstract

SummaryRecent studies have demonstrated that many parasites release extracellular vesicles (EVs), yet little is known about the specific interactions of EVs with immune cells or their functions during infection. We show that EVs secreted by the gastrointestinal nematode Heligmosomoides polygyrus are internalized by macrophages and modulate their activation. EV internalization causes downregulation of type 1 and type 2 immune-response-associated molecules (IL-6 and TNF, and Ym1 and RELMα) and inhibits expression of the IL-33 receptor subunit ST2. Co-incubation with EV antibodies abrogated suppression of alternative activation and was associated with increased co-localization of the EVs with lysosomes. Furthermore, mice vaccinated with EV-alum generated protective immunity against larval challenge, highlighting an important role in vivo. In contrast, ST2-deficient mice are highly susceptible to infection, and they are unable to clear parasites following EV vaccination. Hence, macrophage activation and the IL-33 pathway are targeted by H. polygyrus EVs, while neutralization of EV function facilitates parasite expulsion.

Extracellular vesicles induce protective immunity against Trichuris muris

“…This may be explained by the extensive overlap between proteins identified in EV samples and ES depleted of EVs (Table ). Coakley and colleagues report similar findings, demonstrating that vaccinating mice with H. polygyrus exosomes prior to infection boosted antibody response to ES depleted of EVs, and that rats vaccinated with H. polygyrus EVs make antibodies against EV and ES material in the absence of infection . We measured high levels of antiparasite IgG2a/c in all of the EV vaccinated mice (Figure ), and as such, found no correlation between worm burden and antiparasite IgG2a/c production.…”

“…The protection afforded by these EV vaccinations was variable; sterile immunity was achieved for some individuals, while others developed chronic infection. This has also been reported for H. polygyrus EV vaccinations, although in these experiments, mice were vaccinated with 10 μg of material, boosted twice with 2 μg material, and all vaccinations were formulated with alum adjuvant, 20 whereas the vaccinations performed here contained less material and were formulated without adjuvant. Effective EV vaccination without adjuvant has been shown for other pathogen systems highlighting the inherent immunogenicity of EVs containing protein antigens compared to proteins or peptides alone.…”

“…This is the first example of successful vaccination against a Trichuris parasite using EVs, and the first example of an EV vaccination formulated without adjuvant. Recent reports have demonstrated that vaccination with H. polygyrus EVs can protect mice against a subsequent infection, while vaccinating mice with E. caproni EVs can improve the clinical outcome of infection . There are also a number of examples of protective immunity induced by vaccination with EVs derived from host cells, for example, vaccinating CBA/J mice with EVs collected from splenic DCs pulsed with T. gondii antigens before pregnancy induced protective immunity in pups, resulting in fewer brain cysts and lower mortality following congenital exposure .…”

“…The soluble material released by T. muris , known as the ES, has formed the basis of experimental vaccines in mice, while EVs remain a relatively unexplored source of host protective antigens. Recently, there has been great interest in the ability of parasite‐derived EVs, namely exosomes, to stimulate and/or modulate host immunity and other researchers have demonstrated that vaccination with Heligosomoides polygyrus EVs can protect mice against a subsequent infection . EVs have been isolated from T. muris and T. suis (porcine whipworm) secretions, as well as from other parasitic nematodes such as Brugia malayi …”

Organoids – New Models for Host–Helminth Interactions

“…Cell lines and primary small intestine and colonic epithelial cells have also been used to study the responses of epithelial cells to H. polygyrus [49], T. muris [50,51], T. spiralis [39], and Ascaris ES products and EVs [52]. While the use of cellular preparations ex vivo allows experiments to be performed with the different cell populations present in the tissue, the isolation procedures disrupt the architecture and polarization of the cells in the tissue, making it difficult to interpret the results.…”