Extracellular Vesicles from a Helminth Parasite Suppress Macrophage Activation and Constitute an Effective Vaccine for Protective Immunity
Gillian Coakley,
Jana L. McCaskill,
Jessica G. Borger,
Fabio Simbari,
Elaine Robertson,
Marissa Millar,
Yvonne Harcus,
Henry J. McSorley,
Rick M. Maizels,
Amy H. Buck
Affiliations
Gillian Coakley
Institute of Immunology and Infection Research and Centre for Immunity, Infection & Evolution, School of Biological Sciences, University of Edinburgh, Edinburgh EH9 3FL, UK
Jana L. McCaskill
Institute of Immunology and Infection Research and Centre for Immunity, Infection & Evolution, School of Biological Sciences, University of Edinburgh, Edinburgh EH9 3FL, UK
Jessica G. Borger
Institute of Immunology and Infection Research and Centre for Immunity, Infection & Evolution, School of Biological Sciences, University of Edinburgh, Edinburgh EH9 3FL, UK
Fabio Simbari
Institute of Immunology and Infection Research and Centre for Immunity, Infection & Evolution, School of Biological Sciences, University of Edinburgh, Edinburgh EH9 3FL, UK
Elaine Robertson
Institute of Immunology and Infection Research and Centre for Immunity, Infection & Evolution, School of Biological Sciences, University of Edinburgh, Edinburgh EH9 3FL, UK
Marissa Millar
Institute of Immunology and Infection Research and Centre for Immunity, Infection & Evolution, School of Biological Sciences, University of Edinburgh, Edinburgh EH9 3FL, UK
Yvonne Harcus
Institute of Immunology and Infection Research and Centre for Immunity, Infection & Evolution, School of Biological Sciences, University of Edinburgh, Edinburgh EH9 3FL, UK
Henry J. McSorley
Centre for Inflammation Research, University of Edinburgh, The Queens Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ, UK
Rick M. Maizels
Wellcome Centre for Molecular Parasitology, Institute for Infection, Immunity and Inflammation, Sir Graeme Davies Building, 120 University Place, Glasgow G12 8TA, UK
Amy H. Buck
Institute of Immunology and Infection Research and Centre for Immunity, Infection & Evolution, School of Biological Sciences, University of Edinburgh, Edinburgh EH9 3FL, UK
Recent 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.
