Dr Henry McSorley
Parasitic helminths have co-evolved with their mammalian hosts, resulting in their development of sophisticated methods of immune modulation to allow the parasites to survive despite efforts of the immune response to eject them. Our lab focuses on how parasitic helminths achieve this, identifying factors which modulate the host immune response and characterising their molecular mechanisms of action. By better understanding how helminths modulate the host immune response, we could learn from these sophisticated parasites, and use this knowledge to develop new treatments for immune-mediated diseases such as allergies and asthma. Conversely, by understanding how helminths interact with the immune system, we can understand how to better combat these important pathogens which afflict hundreds of millions of people worldwide.
Heligmosomoides polygyrus adult parasites – a nematode worm which infects mice and lives in the small intestine. These parasites can be up to 1 cm long when stretched out, but usually are tightly coiled as shown.
The Hygiene Hypothesis:
Parasitic helminth infections negatively correlate with the prevalence of allergic immune disease, and as the prevalence of parasitic infections has decreased (due to improvements in sanitation and hygiene) over the last century, we have suffered and epidemic of allergic disease. Parasites achieve this effect through the release of soluble immunodulatory factors which suppress the parasite-toxic type 2 immune response, and as a “side-effect” suppress allergic immune responses.
We recently characterised two of the factors which the murine intestinal parasite Heligmosomoides polygyrus uses to achieve this, both of which act against the IL-33 pathway. HpARI acts against IL-33 (Osbourn, 2017, Immunity), while HpBARI acts against the IL-33 receptor (Vacca, 2020, eLife) as envisaged in the Wormuvian Man diagram, below. IL-33 is also critical in the development of allergic diseases such as asthma, and we are interested in developing these parasite-derived factors as asthma treatments.
The immune modulating activities of H. polygyrus is not limited to IL-33, and we are currently investigating further activities of the parasite against other immune pathways.
Wormuvian man. This diagram shows the H. polygyrus parasite as Da Vinci’s Vitruvian man, in the centre of the immune responses induced against it. H. polygyrus infection causes necrosis of intestinal epithelial cells, and release of IL-33 (bottom). IL-33 activates a range of immune cells such as ILC2s, mast cells, TH2 cells (left), which leads to mucous hypersecretion, remodelling and parasite ejection (shown around the edge of the circle). H. polygyrus secretes HpARI (left hand) which binds IL-33 and DNA, tethering the cytokine within necrotic cells. H. polygyrus also secretes HpBARI (right hand) which binds and blocks ST2, the IL-33 receptor. Due to these (and other) immune modulating activities, the parasite successfully modulates the host immune response and can form chronic infections. Diagram originally conceived by Dr Francesco Vacca, and updated by Hana Pokojna.
IL-33 is an important cytokine in a range of diseases, from parasitic infections and allergies, to colitis, metabolism and tumour immunity. Stemming for our research on how parasite modulation of the IL-33 pathway affects resistance/susceptibility, another focus of our lab is on how IL-33 responses are induced and controlled in the immune system, and how it affects responding immune cells (ILC2, mast cells, Th2 cells, stromal cells) locally and systemically.
- Meiners J, Reitz M, Rüdiger N, Turner JE, Heepmann L, Rudolf L, Hartmann W, McSorley HJ, Breloer M. (2020) IL-33 facilitates rapid expulsion of the parasitic nematode Strongyloides ratti from the intestine via ILC2- and IL-9-driven mast cell activation. PLoS Pathog. 16(12):e1009121. doi: 10.1371/journal.ppat.1009121
- Vacca F, Chauché C, Jamwal A, Hinchy EC, Heieis G, Webster H, Ogunkanbi A, Sekne Z, Gregory WF, Wear M, Perona-Wright G, Higgins MK, Nys JA, Cohen ES, McSorley HJ. 2020. A helminth-derived suppressor of ST2 blocks allergic responses. Elife. 9:e54017. doi: 10.7554/eLife.54017.
- Chauché C, Vacca F, Chia SL, Richards J, Gregory WF, Ogunkanbi A, Wear M, McSorley HJ. 2020. A Truncated Form of HpARI Stabilizes IL-33, Amplifying Responses to the Cytokine. Front Immunol. 11:1363. doi: 10.3389/fimmu.2020.01363.
- Maizels RM, Smits HH, McSorley HJ. (2018) Modulation of Host Immunity by Helminths: The Expanding Repertoire of Parasite Effector Molecules. Immunity. 49:801-818. doi. 10.1016/j.immuni.2018.10.016
- Osbourn M, Soares DC, Vacca F, Cohen ES, Scott IC, Gregory WF, Smyth DJ, Toivakka M, Kemter AM, le Bihan T, Wear M, Hoving D, Filbey KJ, Hewitson JP, Henderson H, Gonzàlez-Cìscar A, Errington C, Vermeren S, Astier AL, Wallace WA, Schwarze J, Ivens AC, Maizels RM, McSorley HJ. (2017) HpARI Protein Secreted by a Helminth Parasite Suppresses Interleukin-33. Immunity. 47:739-751 e735. doi. 10.1016/j.immuni.2017.09.015
- Johnston CJC, Smyth DJ, Kodali RB, White MPJ, Harcus Y, Filbey KJ, Hewitson JP, Hinck CS, Ivens A, Kemter AM, Kildemoes AO, Le Bihan T, Soares DC, Anderton SM, Brenn T, Wigmore SJ, Woodcock HV, Chambers RC, Hinck AP, McSorley HJ, Maizels RM. (2017) A structurally distinct TGF-β mimic from an intestinal helminth parasite potently induces regulatory T cells. Nat Commun. 8(1):1741. doi: 10.1038/s41467-017-01886-6.
- Jackson-Jones LH, Duncan SM, Magalhaes MS, Campbell SM, Maizels RM, McSorley HJ, Allen JE, Bénézech C. (2016) Fat-associated lymphoid clusters control local IgM secretion during pleural infection and lung inflammation. Nat Commun. 7:12651. doi: 10.1038/ncomms12651.
- McSorley HJ, Blair NF, Smith KA, McKenzie AN, Maizels RM. (2014) Blockade of IL-33 release and suppression of type 2 innate lymphoid cell responses by helminth secreted products in airway allergy. Mucosal Immunol. 7:1068-1078. doi. 10.1038/mi.2013.123
- Ferreira I, Smyth D, Gaze S, Aziz A, Giacomin P, Ruyssers N, Artis D, Laha T, Navarro S, Loukas A, McSorley HJ. (2013) Hookworm excretory/secretory products induce interleukin-4 (IL-4)+ IL-10+ CD4+ T cell responses and suppress pathology in a mouse model of colitis. Infect Immun. 81:2104-2111. doi. 10.1128/IAI.00563-12
- McSorley HJ, O'Gorman MT, Blair N, Sutherland TE, Filbey KJ, Maizels RM. (2012). Suppression of type 2 immunity and allergic airway inflammation by secreted products of the helminth Heligmosomoides polygyrus. Eur J Immunol. 42:2667-2682. doi. 10.1002/eji.201142161
A full list of publications can be found on PubMed.gov.