Helminth-derived proteins as immune system regulators: a systematic review of their promise in alleviating colitis

Quinnell RJ. Genetics of susceptibility to human helminth infection. Int J Parasitol. 2003;33:1219–31.

Marquet S, Abel L, Hillaire D, Dessein H, Kalil J, Feingold J, et al. Genetic localization of a locus controlling the intensity of infection by Schistosoma mansoni on chromosome 5q31–q33. Nat Genet. 1996;14:181–4.

Maizels RM, Balic A, Gomez-Escobar N, Nair M, Taylor MD, Allen JE. Helminth parasites - masters of regulation. Immunol Rev. 2004;201:89–116.

Harnett W, Harnett MM, FILARIAL NEMATODE SECRETED PRODUCT, ES-62 IS AN ANTI‐INFLAMMATORY AGENT: THERAPEUTIC POTENTIAL OF SMALL MOLECULE DERIVATIVES AND ES‐62 PEPTIDE MIMETICS. Clin Exp Pharmacol Physiol. 2006;33:511–8.

Maizels RM, McSorley HJ. Regulation of the host immune system by helminth parasites. J Allergy Clin Immunol. 2016;138:666–75.

Weinstock JV. Do we need worms to promote Immune Health? Clin Rev Allergy Immunol. 2015;49:227–31.

Johnston MJG, MacDonald JA, McKay DM. Parasitic helminths: a pharmacopeia of anti-inflammatory molecules. Parasitology. 2009;136:125–47.

Wang M, Wu L, Weng R, Zheng W, Wu Z, Lv Z. Therapeutic potential of helminths in autoimmune diseases: helminth-derived immune-regulators and immune balance. Parasitol Res. 2017;116:2065–74.

Wu Z, Wang L, Tang Y, Sun X. Parasite-derived proteins for the treatment of allergies and Autoimmune diseases. Front Microbiol. 2017;8:2164.

Kaser A, Zeissig S, Blumberg RS. Inflammatory bowel disease. Annu Rev Immunol. 2010;28:573–621.

Berg DJ, Zhang J, Weinstock JV, Ismail HF, Earle KA, Alila H, et al. Rapid development of colitis in NSAID-treated IL-10–deficient mice. Gastroenterology. 2002;123:1527–42.

Ostanin DV, Bao J, Koboziev I, Gray L, Robinson-Jackson SA, Kosloski-Davidson M, et al. T cell transfer model of chronic colitis: concepts, considerations, and tricks of the trade. Am J Physiology-Gastrointestinal Liver Physiol. 2009;296:G135–46.

Wang SS, Xie YY, Yang XD, Wang XS, Yan K, Zhong ZR et al. Therapeutic potential of recombinant cystatin from Schistosoma japonicum in TNBS-induced experimental colitis of mice. Parasit Vectors. 2016;9.

Wirtz S, Neufert C, Weigmann B, Neurath MF. Chemically induced mouse models of intestinal inflammation. Nat Protoc. 2007;2:541–6.

Arai T, Lopes F. Potential of human helminth therapy for resolution of inflammatory bowel disease: the future ahead. Exp Parasitol. 2022;232:108189.

Fleming J, Hernandez G, Hartman L, Maksimovic J, Nace S, Lawler B, et al. Safety and efficacy of helminth treatment in relapsing-remitting multiple sclerosis: results of the HINT 2 clinical trial. Mult Scler. 2019;25:81–91.

Voldsgaard A, Bager P, Garde E, Åkeson P, Leffers AM, Madsen CG, et al. Trichuris suis ova therapy in relapsing multiple sclerosis is safe but without signals of beneficial effect. Mult Scler. 2015;21:1723–9.

Schölmerich J, Fellermann K, Seibold FW, Rogler G, Langhorst J, Howaldt S, et al. A Randomised, Double-blind, placebo-controlled trial of Trichuris suis ova in active Crohn’s Disease. J Crohns Colitis. 2017;11:390–9.

Stroup DF. Meta-analysis of Observational Studies in EpidemiologyA Proposal for Reporting JAMA. 2000;283:2008.

Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. BMJ. 2009;339(jul21 1):b2535–2535.

Hooijmans CR, Rovers MM, de Vries RB, Leenaars M, Ritskes-Hoitinga M, Langendam MW. SYRCLE’s risk of bias tool for animal studies. BMC Med Res Methodol. 2014;14:43.

Khatri V, Amdare N, Tarnekar A, Goswami K, Reddy MVR. Brugia malayi cystatin therapeutically ameliorates dextran sulfate sodium-induced colitis in mice. J Dig Dis. 2015;16:585–94.

Togre NS, Bhoj PS, Khatri VK, Tarnekar A, Goswami K, Shende MR, et al. SXP-RAL family filarial protein, rWbL2, prevents Development of DSS-Induced Acute Ulcerative Colitis. Indian J Clin Biochem. 2018;33:282–9.

Driss V, El Nady M, Delbeke M, Rousseaux C, Dubuquoy C, Sarazin A, et al. The schistosome glutathione S-transferase P28GST, a unique helminth protein, prevents intestinal inflammation in experimental colitis through a Th2-type response with mucosal eosinophils. Mucosal Immunol. 2016;9:322–35.

Wang L, Xie H, Xu L, Liao Q, Wan S, Yu Z, et al. rSj16 protects against DSS-Induced colitis by inhibiting the PPAR-alpha signaling pathway. Theranostics. 2017;7:3446–60.

Sarazin A, Dendooven A, Delbeke M, Gatault S, Pagny A, Standaert A, et al. Treatment with P28GST, a schistosome-derived enzyme, after acute colitis induction in mice: decrease of intestinal inflammation associated with a down regulation of Th1/Th17 responses. PLoS ONE. 2018;13:e0209681.

Ferreira IB, Pickering DA, Troy S, Croese J, Loukas A, Navarro S. Suppression of inflammation and tissue damage by a hookworm recombinant protein in experimental colitis. Clin Transl Immunol. 2017;6.

Buitrago G, Pickering D, Ruscher R, Cobos Caceres C, Jones L, Cooper M, et al. A netrin domain-containing protein secreted by the human hookworm Necator americanus protects against CD4 T cell transfer colitis. Transl Res. 2021;232:88–102.

Smallwood TB, Navarro S, Cristofori-Armstrong B, Watkins TS, Tungatt K, Ryan RYM et al. Synthetic hookworm-derived peptides are potent modulators of primary human immune cell function that protect against experimental colitis in vivo. J Biol Chem. 2021;297.

Coronado S, Barrios L, Zakzuk J, Regino R, Ahumada V, Franco L, et al. A recombinant cystatin from Ascaris lumbricoides attenuates inflammation of DSS-induced colitis. Parasite Immunol. 2017;39:4.

Du L, Tang H, Ma Z, Xu J, Gao W, Chen J, et al. The protective effect of the recombinant 53-kDa protein of Trichinella spiralis on experimental colitis in mice. Dig Dis Sci. 2011;56:2810–7.

Qu Z, Jin X, Wang Y, Yang Y, Yang L, Bai X, et al. Effect of recombinant serine protease from newborn larval stage of Trichinella spiralis on 2,4,6-trinitrobenzene sulfonic acid-induced experimental colitis in mice. Acta Trop. 2020;211:105553.

Xu J, Wu L, Yu P, Liu M, Lu Y. Effect of two recombinant trichinella spiralis serine protease inhibitors on TNBS-induced experimental colitis of mice. Clin Exp Immunol. 2018;194:400–13.

Hao C, Wang W, Zhan B, Wang Z, Huang J, Sun X et al. Trichinella spiralis Paramyosin Induces Colonic Regulatory T Cells to Mitigate Inflammatory Bowel Disease. Front Cell Dev Biol. 2021;9 (no pagination).

Jang SW, Cho MK, Park MK, Kang SA, Na BK, Ahn SC, et al. Parasitic helminth cystatin inhibits DSS-induced intestinal inflammation via IL-10(+)F4/80(+) macrophage recruitment. Korean J Parasitol. 2011;49:245–54.

Fleming JO, Weinstock JV. Clinical trials of helminth therapy in autoimmune diseases: Rationale and findings. Parasite Immunol. 2015;37:277–92.

Heylen M, Ruyssers NE, De Man JG, Timmermans JP, Pelckmans PA, Moreels TG, et al. Worm proteins of Schistosoma mansoni reduce the severity of experimental chronic colitis in mice by suppressing colonic proinflammatory immune responses. PLoS ONE [Electronic Resource]. 2014;9:e110002.

Ruyssers NE, De Winter BY, De Man JG, Loukas A, Pearson MS, Weinstock JV, et al. Therapeutic potential of Helminth Soluble Proteins in TNBS-induced colitis in mice. Inflamm Bowel Dis. 2009;15:491–500.

Wangchuk P, Shepherd C, Constantinoiu C, Ryan RYM, Kouremenos KA, Becker L, et al. Hookworm-derived metabolites suppress Pathology in a mouse model of colitis and inhibit secretion of Key Inflammatory cytokines in Primary Human leukocytes. Infect Immun. 2019;87:4.

Smallwood TB, Navarro S, Cristofori-Armstrong B, Watkins TS, Tungatt K, Ryan RYM, et al. Synthetic hookworm-derived peptides are potent modulators of primary human immune cell function that protect against experimental colitis in vivo. J Biol Chem. 2021;297:100834.

Ferreira I, Smyth D, Gaze S, Aziz A, Giacomin P, Ruyssers N, et al. 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. 2013;81(6):2104–11.

Cancado GGL, Fiuza JA, de Paiva NCN, Lemos LDD, Ricci ND, Gazzinelli-Guimaraes PH, et al. Hookworm products ameliorate Dextran Sodium Sulfate-induced colitis in BALB/c mice. Inflamm Bowel Dis. 2011;17:2275–86.

Loukas A, Prociv P. Immune responses in hookworm infections. Clin Microbiol Rev. 2001;14.

Riganò R, Buttari B, Profumo E, Ortona E, Delunardo F, Margutti P, et al. Echinococcus Granulosus Antigen B impairs human dendritic cell differentiation and polarizes immature dendritic cell maturation towards a Th2 cell response. Infect Immun. 2007;75:1667–78.

Kawai T, Akira S. TLR signaling. Cell Death Differ. 2006;13:816–25.

Nono JK, Pletinckx K, Lutz MB, Brehm K. Excretory/secretory-products of Echinococcus multilocularis larvae induce apoptosis and tolerogenic properties in dendritic cells in vitro. PLoS Negl Trop Dis. 2012;6:e1516.

Harn DA, McDonald J, Atochina O, Da’dara AA. Modulation of host immune responses by helminth glycans. Immunol Rev. 2009;230:247–57.

van Riet E, Everts B, Retra K, Phylipsen M, van Hellemond JJ, Tielens AGM, et al. Combined TLR2 and TLR4 ligation in the context of bacterial or helminth extracts in human monocyte derived dendritic cells: molecular correlates for Th1/Th2 polarization. BMC Immunol. 2009;10:9.

Cvetkovic J, Sofronic-Milosavljevic L, Ilic N, Gnjatovic M, Nagano I, Gruden-Movsesijan A. Immunomodulatory potential of particular Trichinella spiralis muscle larvae excretory-secretory components. Int J Parasitol. 2016;46:833–42.

Bai X, Wu X, Wang X, Guan Z, Gao F, Yu J, et al. Regulation of cytokine expression in murine macrophages stimulated by excretory/secretory products from Trichinella spiralis in vitro. Mol Cell Biochem. 2012;360:79–88.

Donnelly S, O’Neill SM, Stack CM, Robinson MW, Turnbull L, Whitchurch C, et al. Helminth cysteine proteases inhibit TRIF-dependent activation of macrophages via degradation of TLR3. J Biol Chem. 2010;285:3383–92.

Everts B, Hussaarts L, Driessen NN, Meevissen MHJ, van der Schramm G, et al. Schistosome-derived omega-1 drives Th2 polarization by suppressing protein synthesis following internalization by the mannose receptor. J Exp Med. 2012;209:1753–67. S1.

Schierack P, Lucius R, Sonnenburg B, Schilling K, Hartmann S. Parasite-specific immunomodulatory functions of filarial cystatin. Infect Immun. 2003;71:2422–9.

Donahue PE, Samelson S, Nyhus LM, Bombeck CT. The floppy Nissen fundoplication. Effective long-term control of pathologic reflux. Arch Surg. 1985;120:663–8.

Cooper D, Eleftherianos I. Parasitic nematode immunomodulatory strategies: recent advances and perspectives. Pathogens. 2016;5:58.

Hartmann S, Lucius R. Modulation of host immune responses by nematode cystatins. Int J Parasitol. 2003;33:1291–302.

Manoury B, Gregory WF, Maizels RM, Watts C. Bm-CPI-2, a cystatin homolog secreted by the filarial parasite Brugia Malayi, inhibits class II MHC-restricted antigen processing. Curr Biol. 2001;11:447–51.

Ziegler T, Rausch S, Steinfelder S, Klotz C, Hepworth MR, Kühl AA, et al. A Novel Regulatory Macrophage Induced by a Helminth Molecule instructs IL-10 in CD4 + T cells and protects against mucosal inflammation. J Immunol. 2015;194:1555–64.

Xu N, Bai X, Liu Y, Yang Y, Tang B, Shi HN, et al. The anti-inflammatory Immune response in early trichinella spiralis intestinal infection depends on serine protease inhibitor-mediated alternative activation of macrophages. J Immunol. 2021;206:963–77.

Liu W, Liu J, Wu J, Zhang L, Liu F, Yin L, et al. Novel mechanism of inhibition of dendritic cells maturation by mesenchymal stem cells via Interleukin-10 and the JAK1/STAT3 signaling pathway. PLoS ONE. 2013;8:e55487.

Hosken NA, Shibuya K, Heath AW, Murphy KM, O’Garra A. The effect of antigen dose on CD4 + T helper cell phenotype development in a T cell receptor-alpha beta-transgenic model. J Exp Med. 1995;182:1579–84.

Johnston CJC, Smyth DJ, Dresser DW, Maizels RM. TGF-β in tolerance, development and regulation of immunity. Cell Immunol. 2016;299:14–22.