Hostname: page-component-586b7cd67f-vdxz6 Total loading time: 0 Render date: 2024-11-22T16:16:23.743Z Has data issue: false hasContentIssue false
  • English
  • Français

Helminth-derived cystatins: the immunomodulatory properties of an Ascaris lumbricoides cystatin

Published online by Cambridge University Press:  10 February 2021

Luis Caraballo Open the ORCID record for Luis Caraballo [Opens in a new window] ,
Josefina Zakzuk  and
Nathalie Acevedo
Luis Caraballo*
Affiliation:
Institute for Immunological Research, University of Cartagena, Cartagena de Indias, Colombia
Josefina Zakzuk
Affiliation:
Institute for Immunological Research, University of Cartagena, Cartagena de Indias, Colombia
Nathalie Acevedo
Affiliation:
Institute for Immunological Research, University of Cartagena, Cartagena de Indias, Colombia
*
Author for correspondence: Luis Caraballo, E-mail: [email protected]
Get access Rights & Permissions [Opens in a new window]

Abstract

Helminth infections such as ascariasis elicit a type 2 immune response resembling that involved in allergic inflammation, but differing to allergy, they are also accompanied with strong immunomodulation. This has stimulated an increasing number of investigations, not only to better understand the mechanisms of allergy and helminth immunity but to find parasite-derived anti-inflammatory products that could improve the current treatments of chronic non-communicable inflammatory diseases such as asthma. A great number of helminth-derived immunomodulators have been discovered and some of them extensively analysed, showing their potential use as anti-inflammatory drugs in clinical settings. Since Ascaris lumbricoides is one of the most successful parasites, several groups have focused on the immunomodulatory properties of this helminth. As a result, several excretory/secretory components and purified molecules have been analysed, revealing interesting anti-inflammatory activities potentially useful as therapeutic tools. One of these molecules is A. lumbricoides cystatin, whose genomic, cellular, molecular, and immunomodulatory properties are described in this review.

Keywords

AllergyascariasisAscarisasthmacolitiscystatinIgEimmunomodulationinflammatory non-communicable diseasesmouse modelrespiratory
Type
Review Article
Information
Parasitology , Volume 148 , Special Issue 14: Lessons from studying roundworm and whipworm in the mouse - common themes and unique features , December 2021 , pp. 1744 - 1756
Check for updates
Copyright
Copyright © The Author(s), 2021. Published by Cambridge University Press

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

Almeida, S, Nejsum, P and Williams, AR (2018) Modulation of human macrophage activity by Ascaris antigens is dependent on macrophage polarization state. Immunobiology 223, 405–412.10.1016/j.imbio.2017.11.003CrossRefGoogle ScholarPubMed
Amin, F, Khan, MS and Bano, B (2020) Mammalian cystatin and protagonists in brain diseases. Journal of Biomolecular Structure & Dynamics 38, 2171–2196.10.1080/07391102.2019.1620636CrossRefGoogle ScholarPubMed
Antunes, MF, Titz, TO, Batista, IF, Marques-Porto, R, Oliveira, CF, Alves de Araujo, CA and Macedo-Soares, MF (2015) Immunosuppressive PAS-1 is an excretory/secretory protein released by larval and adult worms of the ascarid nematode Ascaris suum. Journal of Helminthology 89, 367–374.10.1017/S0022149X14000200CrossRefGoogle ScholarPubMed
Araujo, CA, Perini, A, Martins, MA, Macedo, MS and Macedo-Soares, MF (2008) PAS-1, a protein from Ascaris suum, modulates allergic inflammation via IL-10 and IFN-gamma, but not IL-12. Cytokine 44, 335–341.10.1016/j.cyto.2008.09.005CrossRefGoogle Scholar
Bach, JF (2002) The effect of infections on susceptibility to autoimmune and allergic diseases. New England Journal of Medicine 347, 911–920.10.1056/NEJMra020100CrossRefGoogle ScholarPubMed
Barriga, OO (1984) Immunomodulation by nematodes: a review. Veterinary Parasitology 14, 299–320.10.1016/0304-4017(84)90098-0CrossRefGoogle ScholarPubMed
Bourke, CD, Maizels, RM and Mutapi, F (2011) Acquired immune heterogeneity and its sources in human helminth infection. Parasitology 138, 139–159.10.1017/S0031182010001216CrossRefGoogle ScholarPubMed
Bush, A, Kleinert, S and Pavord, ID (2015) The asthmas in 2015 and beyond: a Lancet Commission. Lancet 385, 1273–1275.10.1016/S0140-6736(15)60654-7CrossRefGoogle ScholarPubMed
Caraballo, L (2013) Ascaris and allergy. In Holland, CV (ed.), Ascaris: The Neglected Parasite. London, UK: Elsevier, pp. 21–50.10.1016/B978-0-12-396978-1.00002-1CrossRefGoogle Scholar
Caraballo, L (2018) The tropics, helminth infections and hygiene hypotheses. Expert Review of Clinical Immunology 14, 99–102.10.1080/1744666X.2018.1424543CrossRefGoogle ScholarPubMed
Caraballo, L, Acevedo, N and Zakzuk, J (2019) Ascariasis as a model to study the helminth/allergy relationships. Parasite Immunology 41, e12595.10.1111/pim.12595CrossRefGoogle Scholar
Caraballo, L, Valenta, R, Puerta, L, Pomes, A, Zakzuk, J, Fernandez-Caldas, E, Acevedo, N, Sanchez-Borges, M, Ansotegui, I, Zhang, L, van Hage, M, Fernandez, E, Arruda, L, Vrtala, S, Curin, M, Gronlund, H, Karsonova, A, Kilimajer, J, Riabova, K, Trifonova, D and Karaulov, A (2020) The allergenic activity and clinical impact of individual IgE-antibody binding molecules from indoor allergen sources. The World Allergy Organization Journal 13, 100118.10.1016/j.waojou.2020.100118CrossRefGoogle ScholarPubMed
Cardoso, V, Chesne, J, Ribeiro, H, Garcia-Cassani, B, Carvalho, T, Bouchery, T, Shah, K, Barbosa-Morais, NL, Harris, N and Veiga-Fernandes, H (2017) Neuronal regulation of type 2 innate lymphoid cells via neuromedin U. Nature 549, 277–281.10.1038/nature23469CrossRefGoogle ScholarPubMed
Chehayeb, JF, Robertson, AP, Martin, RJ and Geary, TG (2014) Proteomic analysis of adult Ascaris suum fluid compartments and secretory products. PLoS Neglected Tropical Diseases 8, e2939.10.1371/journal.pntd.0002939CrossRefGoogle ScholarPubMed
Cooper, PJ, Chico, ME, Sandoval, C, Espinel, I, Guevara, A, Kennedy, MW, Urban, JF Jr, Griffin, GE and Nutman, TB (2000) Human infection with Ascaris lumbricoides is associated with a polarized cytokine response. Journal of Infectious Diseases 182, 1207–1213.10.1086/315830CrossRefGoogle ScholarPubMed
Cooper, PJ, Chico, M, Sandoval, C, Espinel, I, Guevara, A, Levine, MM, Griffin, GE and Nutman, TB (2001) Human infection with Ascaris lumbricoides is associated with suppression of the interleukin-2 response to recombinant cholera toxin B subunit following vaccination with the live oral cholera vaccine CVD 103-HgR. Infection and Immunity 69, 1574–1580.10.1128/IAI.69.3.1574-1580.2001CrossRefGoogle ScholarPubMed
Cooper, PJ, Moncayo, AL, Guadalupe, I, Benitez, S, Vaca, M, Chico, M and Griffin, GE (2008) Repeated treatments with albendazole enhance Th2 responses to Ascaris lumbricoides, but not to aeroallergens, in children from rural communities in the Tropics. Journal of Infectious Diseases 198, 1237–1242.10.1086/591945CrossRefGoogle Scholar
Cooper, PJ, Chico, ME, Vaca, MG, Sandoval, CA, Loor, S, Amorim, L, Rodrigues, LC, Barreto, ML and Strachan, DP (2017) Effect of early life geohelminth infections on the development of wheezing at 5 years of age. American Journal of Respiratory and Critical Care Medicine 197, 364–372.10.1164/rccm.201706-1222OCCrossRefGoogle Scholar
Coronado, S, Manotas, M, Zakzuk, J and Caraballo, L (2015) Ascaris lumbricoides cystatin induces specific IgE but not allergic response. Frontiers in Immunology. Conference Abstract: IMMUNOCOLOMBIA2015 ‐ 11th Congress of the Latin American Association of Immunology ‐ 10o. Congreso de la Asociación Colombiana de Alergia, Asma e Inmunología. doi: 10.3389/conf.fimmu.2015.05.00295Google Scholar
Coronado, S, Barrios, L, Zakzuk, J, Regino, R, Ahumada, V, Franco, L, Ocampo, Y and Caraballo, L (2017) A recombinant cystatin from Ascaris lumbricoides attenuates inflammation of DSS-induced colitis. Parasite Immunology 39, 1–10.10.1111/pim.12425CrossRefGoogle ScholarPubMed
Coronado, S, Zakzuk, J, Regino, R, Ahumada, V, Benedetti, I, Angelina, A, Palomares, O and Caraballo, L (2019) Ascaris lumbricoides cystatin prevents development of allergic airway inflammation in a mouse model. Frontiers in Immunology 10, 2280.10.3389/fimmu.2019.02280CrossRefGoogle ScholarPubMed
Dainichi, T, Maekawa, Y, Ishii, K, Zhang, T, Fawzy Nashed, B, Sakai, T, Takashima, M and Himeno, K (2001) Nippocystatin, a cysteine protease inhibitor from Nippostrongylus brasiliensis, inhibits antigen processing and modulates antigen-specific immune response. Infection and Immunity 69, 7380–7386.10.1128/IAI.69.12.7380-7386.2001CrossRefGoogle ScholarPubMed
Danilowicz-Luebert, E, Steinfelder, S, Kuhl, AA, Drozdenko, G, Lucius, R, Worm, M, Hamelmann, E and Hartmann, S (2013) A nematode immunomodulator suppresses grass pollen-specific allergic responses by controlling excessive Th2 inflammation. International Journal for Parasitology 43, 201–210.10.1016/j.ijpara.2012.10.014CrossRefGoogle ScholarPubMed
Dawson, HD, Beshah, E, Nishi, S, Solano-Aguilar, G, Morimoto, M, Zhao, A, Madden, KB, Ledbetter, TK, Dubey, JP, Shea-Donohue, T, Lunney, JK and Urban, JF (2005) Localized multigene expression patterns support an evolving Th1/Th2-like paradigm in response to infections with Toxoplasma gondii and Ascaris suum. Infection and Immunity 73, 1116–1128.10.1128/IAI.73.2.1116-1128.2005CrossRefGoogle ScholarPubMed
Deehan, MR, Goodridge, HS, Blair, D, Lochnit, G, Dennis, RD, Geyer, R, Harnett, MM and Harnett, W (2002) Immunomodulatory properties of Ascaris suum glycosphingolipids – phosphorylcholine and non-phosphorylcholine-dependent effects. Parasite Immunology 24, 463–469.10.1046/j.1365-3024.2002.00489.xCrossRefGoogle ScholarPubMed
de Ruiter, K, Jochems, SP, Tahapary, DL, Stam, KA, Konig, M, van Unen, V, Laban, S, Hollt, T, Mbow, M, Lelieveldt, BPF, Koning, F, Sartono, E, Smit, JWA, Supali, T and Yazdanbakhsh, M (2020) Helminth infections drive heterogeneity in human type 2 and regulatory cells. Science Translational Medicine 12, 1–16.10.1126/scitranslmed.aaw3703CrossRefGoogle ScholarPubMed
Deslyper, G, Colgan, TJ, Cooper, AJ, Holland, CV and Carolan, JC (2016) A proteomic investigation of hepatic resistance to Ascaris in a murine model. PLoS neglected Tropical Diseases 10, e0004837.10.1371/journal.pntd.0004837CrossRefGoogle ScholarPubMed
Dold, C, Cassidy, JP, Stafford, P, Behnke, JM and Holland, CV (2010) Genetic influence on the kinetics and associated pathology of the early stage (intestinal-hepatic) migration of Ascaris suum in mice. Parasitology 137, 173–185.10.1017/S0031182009990850CrossRefGoogle ScholarPubMed
Dowling, DJ, Noone, CM, Adams, PN, Vukman, KV, Molloy, SF, Forde, J, Asaolu, S and O'Neill, SM (2011) Ascaris lumbricoides pseudocoelomic body fluid induces a partially activated dendritic cell phenotype with Th2 promoting ability in vivo. International Journal for Parasitology 41, 255–261.10.1016/j.ijpara.2010.09.007CrossRefGoogle ScholarPubMed
Enobe, CS, Araujo, CA, Perini, A, Martins, MA, Macedo, MS and Macedo-Soares, MF (2006) Early stages of Ascaris suum induce airway inflammation and hyperreactivity in a mouse model. Parasite Immunology 28, 453–461.10.1111/j.1365-3024.2006.00892.xCrossRefGoogle ScholarPubMed
Eriksen, L, Andersen, S, Nielsen, K, Pedersen, A and Nielsen, J (1980) Experimental Ascaris suum infection in pigs. Serological response, eosinophilia in peripheral blood, occurrence of white spots in the liver and worm recovery from the intestine. Nordisk Veterinaermedicin 32, 233–242.Google ScholarPubMed
Everts, B, Hussaarts, L, Driessen, NN, Meevissen, MH, Schramm, G, van der Ham, AJ, van der Hoeven, B, Scholzen, T, Burgdorf, S, Mohrs, M, Pearce, EJ, Hokke, CH, Haas, H, Smits, HH and Yazdanbakhsh, M (2012) Schistosome-derived omega-1 drives Th2 polarization by suppressing protein synthesis following internalization by the mannose receptor. Journal of Experimental Medicine 209, 1753–1767, S1751.10.1084/jem.20111381CrossRefGoogle ScholarPubMed
Faquim-Mauro, EL and Macedo, MS (1998) The immunosuppressive activity of Ascaris suum is due to high molecular weight components. Clinical and Experimental Immunology 114, 245–251.10.1046/j.1365-2249.1998.00723.xCrossRefGoogle ScholarPubMed
Figueiredo, CA, Barreto, ML, Rodrigues, LC, Cooper, PJ, Silva, NB, Amorim, LD and Alcantara-Neves, NM (2010) Chronic intestinal helminth infections are associated with immune hyporesponsiveness and induction of a regulatory network. Infection and Immunity 78, 3160–3167.10.1128/IAI.01228-09CrossRefGoogle ScholarPubMed
Geadkaew, A, Kosa, N, Siricoon, S, Grams, SV and Grams, R (2014) A 170 kDa multi-domain cystatin of Fasciola gigantica is active in the male reproductive system. Molecular and Biochemical Parasitology 196, 100–107.10.1016/j.molbiopara.2014.08.004CrossRefGoogle Scholar
Geiger, SM, Massara, CL, Bethony, J, Soboslay, PT, Carvalho, OS and Correa-Oliveira, R (2002) Cellular responses and cytokine profiles in Ascaris lumbricoides and Trichuris trichiura infected patients. Parasite Immunology 24, 499–509.10.1046/j.1365-3024.2002.00600.xCrossRefGoogle ScholarPubMed
Gerbe, F, Sidot, E, Smyth, DJ, Ohmoto, M, Matsumoto, I, Dardalhon, V, Cesses, P, Garnier, L, Pouzolles, M, Brulin, B, Bruschi, M, Harcus, Y, Zimmermann, VS, Taylor, N, Maizels, RM and Jay, P (2016) Intestinal epithelial tuft cells initiate type 2 mucosal immunity to helminth parasites. Nature 529, 226–230.10.1038/nature16527CrossRefGoogle ScholarPubMed
Gerrard, JW, Geddes, CA, Reggin, PL, Gerrard, CD and Horne, S (1976) Serum IgE levels in white and metis communities in Saskatchewan. Annals of Allergy 37, 91–100.Google ScholarPubMed
Giacomin, PR, Gordon, DL, Botto, M, Daha, MR, Sanderson, SD, Taylor, SM and Dent, LA (2008) The role of complement in innate, adaptive and eosinophil-dependent immunity to the nematode Nippostrongylus brasiliensis. Molecular Immunology 45, 446–455.10.1016/j.molimm.2007.05.029CrossRefGoogle Scholar
Giera, M, Kaisar, MMM, Derks, RJE, Steenvoorden, E, Kruize, YCM, Hokke, CH, Yazdanbakhsh, M and Everts, B (2018) The Schistosoma mansoni lipidome: leads for immunomodulation. Analytica Chimica Acta 1037, 107–118.10.1016/j.aca.2017.11.058CrossRefGoogle ScholarPubMed
Greenwood, BM (1968) Autoimmune disease and parasitic infections in Nigerians. Lancet 2, 380–382.10.1016/S0140-6736(68)90595-3CrossRefGoogle ScholarPubMed
Guadalupe, I, Mitre, E, Benitez, S, Chico, ME, Nutman, TB and Cooper, PJ (2009) Evidence for in utero sensitization to Ascaris lumbricoides in newborns of mothers with ascariasis. Journal of Infectious Diseases 199, 1846–1850.10.1086/599214CrossRefGoogle ScholarPubMed
Guo, A (2015) Comparative analysis of cystatin superfamily in platyhelminths. PLoS ONE 10, e0124683.10.1371/journal.pone.0124683CrossRefGoogle ScholarPubMed
Hagel, I, Cabrera, M, Puccio, F, Santaella, C, Buvat, E, Infante, B, Zabala, M, Cordero, R and Di Prisco, MC (2011) Co-infection with Ascaris lumbricoides modulates protective immune responses against Giardia duodenalis in school Venezuelan rural children. Acta Tropica 117, 189–195.10.1016/j.actatropica.2010.12.001CrossRefGoogle ScholarPubMed
Hamid, F, Versteeg, SA, Wiria, AE, Wammes, LJ, Wahyuni, S, Supali, T, Sartono, E, van Ree, R and Yazdanbakhsh, M (2017) Molecular diagnostics and lack of clinical allergy in helminth-endemic areas in Indonesia. Journal of Allergy and Clinical Immunology 140, 1196–1199 e1196.10.1016/j.jaci.2017.04.040CrossRefGoogle ScholarPubMed
Hansen, EP, Fromm, B, Andersen, SD, Marcilla, A, Andersen, KL, Borup, A, Williams, AR, Jex, AR, Gasser, RB, Young, ND, Hall, RS, Stensballe, A, Ovchinnikov, V, Yan, Y, Fredholm, M, Thamsborg, SM and Nejsum, P (2019) Exploration of extracellular vesicles from Ascaris suum provides evidence of parasite-host cross talk. Journal of Extracellular Vesicles 8, 1578116.10.1080/20013078.2019.1578116CrossRefGoogle ScholarPubMed
Hartmann, S, Kyewski, B, Sonnenburg, B and Lucius, R (1997) A filarial cysteine protease inhibitor down-regulates T cell proliferation and enhances interleukin-10 production. European Journal of Immunology 27, 2253–2260.10.1002/eji.1830270920CrossRefGoogle ScholarPubMed
Hartmann, S, Schönemeyer, A, Sonnenburg, B, Vray, B and Lucius, R (2002) Cystatins of filarial nematodes up-regulate the nitric oxide production of interferon-γ-activated murine macrophages. Parasite Immunology 24, 253–262.10.1046/j.1365-3024.2002.00459.xCrossRefGoogle ScholarPubMed
Hartmann, S, Sollwedel, A, Hoffmann, A, Sonnenburg, B and Lucius, R (2003) Characterization of IgE responses in a rodent model of filariasis and the allergenic potential of filarial antigens using an in vitro assay. Parasite Immunology 25, 9–16.10.1046/j.1365-3024.2003.00496.xCrossRefGoogle Scholar
Herbert, DR, Douglas, B and Zullo, K (2019) Group 2 innate lymphoid cells (ILC2): type 2 immunity and helminth immunity. International Journal of Molecular Sciences 20, 2276.10.3390/ijms20092276CrossRefGoogle ScholarPubMed
Holland, CV, Behnke, JM and Dold, C (2013) Larval ascariasis: impact, significance, and model organisms. In Ascaris Holland, C (ed.), The Neglected Parasite. London UK: Academic Press, pp. 108–119.Google Scholar
Homan, EJ and Bremel, RD (2018) A role for epitope networking in immunomodulation by helminths. Frontiers in Immunology 9, 1763.10.3389/fimmu.2018.01763CrossRefGoogle ScholarPubMed
Hossny, E, Caraballo, L, Casale, T, El-Gamal, Y and Rosenwasser, L (2017) Severe asthma and quality of life. The World Allergy Organization Journal 10, 28.10.1186/s40413-017-0159-yCrossRefGoogle ScholarPubMed
Hunt, VL, Tsai, IJ, Selkirk, ME and Viney, M (2017) The genome of Strongyloides spp. gives insights into protein families with a putative role in nematode parasitism. Parasitology 144, 343–358.10.1017/S0031182016001554CrossRefGoogle ScholarPubMed
Ichikawa, K, Vailes, L, Pomes, A and Chapman, M (2001) Molecular cloning, expression and modelling of cat allergen, cystatin (Fel d 3), a cysteine protease inhibitor. Clinical & Experimental Allergy 31, 1279–1286.10.1046/j.1365-2222.2001.01169.xCrossRefGoogle Scholar
Ilgova, J, Jedlickova, L, Dvorakova, H, Benovics, M, Mikes, L, Janda, L, Vorel, J, Roudnicky, P, Potesil, D, Zdrahal, Z, Gelnar, M and Kasny, M (2017) A novel type I cystatin of parasite origin with atypical legumain-binding domain. Scientific Reports 7, 17526.10.1038/s41598-017-17598-2CrossRefGoogle ScholarPubMed
Itami, DM, Oshiro, TM, Araujo, CA, Perini, A, Martins, MA, Macedo, MS and Macedo-Soares, MF (2005) Modulation of murine experimental asthma by Ascaris suum components. Clinical and Experimental Allergy 35, 873–879.10.1111/j.1365-2222.2005.02268.xCrossRefGoogle ScholarPubMed
Jang, SW, Cho, MK, Park, MK, Kang, SA, Na, BK, Ahn, SC, Kim, DH and Yu, HS (2011) Parasitic helminth cystatin inhibits DSS-induced intestinal inflammation via IL-10(+)F4/80(+) macrophage recruitment. Korean Journal of Parasitology 49, 245–254.10.3347/kjp.2011.49.3.245CrossRefGoogle ScholarPubMed
Jex, AR, Liu, S, Li, B, Young, ND, Hall, RS, Li, Y, Yang, L, Zeng, N, Xu, X, Xiong, Z, Chen, F, Wu, X, Zhang, G, Fang, X, Kang, Y, Anderson, GA, Harris, TW, Campbell, BE, Vlaminck, J, Wang, T, Cantacessi, C, Schwarz, EM, Ranganathan, S, Geldhof, P, Nejsum, P, Sternberg, PW, Yang, H, Wang, J, Wang, J and Gasser, RB (2011) Ascaris suum draft genome. Nature 479, 529–533.10.1038/nature10553CrossRefGoogle ScholarPubMed
Ji, P, Hu, H, Yang, X, Wei, X, Zhu, C, Liu, J, Feng, Y, Yang, F, Okanurak, K, Li, N, Zeng, X, Zheng, H, Wu, Z and Lv, Z (2015) Accystatin, an immunoregulatory molecule from Angiostrongylus cantonensis, ameliorates the asthmatic response in an aluminium hydroxide/ovalbumin-induced rat model of asthma. Parasitology Research 114, 613–624.10.1007/s00436-014-4223-zCrossRefGoogle Scholar
Jungersen, G, Eriksen, L, Roepstorff, A, Lind, P, Meeusen, EN, Rasmussen, T and Nansen, P (1999) Experimental Ascaris suum infection in the pig: protective memory response after three immunizations and effect of intestinal adult worm population. Parasite Immunology 21, 619–630.10.1046/j.1365-3024.1999.00261.xCrossRefGoogle ScholarPubMed
Kean, DE, Ohtsuka, I, Sato, K, Hada, N, Takeda, T, Lochnit, G, Geyer, R, Harnett, MM and Harnett, W (2006) Dissecting Ascaris glycosphingolipids for immunomodulatory moieties – the use of synthetic structural glycosphingolipid analogues. Parasite Immunology 28, 69–76.10.1111/j.1365-3024.2005.00801.xCrossRefGoogle ScholarPubMed
Khatri, V, Chauhan, N and Kalyanasundaram, R (2020) Parasite cystatin: immunomodulatory molecule with therapeutic activity against immune mediated disorders. Pathogens 9, 1–16.10.3390/pathogens9060431CrossRefGoogle ScholarPubMed
King, EM, Kim, HT, Dang, NT, Michael, E, Drake, L, Needham, C, Haque, R, Bundy, DA and Webster, JP (2005) Immuno-epidemiology of Ascaris lumbricoides infection in a high transmission community: antibody responses and their impact on current and future infection intensity. Parasite Immunology 27, 89–96.10.1111/j.1365-3024.2005.00753.xCrossRefGoogle Scholar
Klotz, C, Ziegler, T, Danilowicz-Luebert, E and Hartmann, S (2011a) Cystatins of parasitic organisms. Advances in Experimental Medicine and Biology 712, 208–221.10.1007/978-1-4419-8414-2_13CrossRefGoogle Scholar
Klotz, C, Ziegler, T, Figueiredo, AS, Rausch, S, Hepworth, MR, Obsivac, N, Sers, C, Lang, R, Hammerstein, P and Lucius, R (2011b) A helminth immunomodulator exploits host signaling events to regulate cytokine production in macrophages. PLoS Pathogens 7, e1001248.10.1371/journal.ppat.1001248CrossRefGoogle Scholar
Kobpornchai, P, Flynn, RJ, Reamtong, O, Rittisoonthorn, N, Kosoltanapiwat, N, Boonnak, K, Ampawong, S, Jiratanh, M, Tattiyapong, M and Adisakwattana, P (2020) A novel cystatin derived from Trichinella spiralis suppresses macrophage-mediated inflammatory responses. PLoS Neglected Tropical Diseases 14, e0008192.10.1371/journal.pntd.0008192CrossRefGoogle ScholarPubMed
Kordis, D and Turk, V (2009) Phylogenomic analysis of the cystatin superfamily in eukaryotes and prokaryotes. BMC Evolutionary Biology 9, 266.10.1186/1471-2148-9-266CrossRefGoogle ScholarPubMed
Labeaud, AD, Malhotra, I, King, MJ, King, CL and King, CH (2009) Do antenatal parasite infections devalue childhood vaccination? PLoS Neglected Tropical Diseases 3, e442.10.1371/journal.pntd.0000442CrossRefGoogle ScholarPubMed
Lee, TD and Xie, CY (1995) Ige regulation by nematodes: the body fluid of Ascaris contains a B-cell mitogen. Journal of Allergy and Clinical Immunology 95, 1246–1254.10.1016/S0091-6749(95)70082-XCrossRefGoogle ScholarPubMed
Lee, C, Bongcam-Rudloff, E, Sollner, C, Jahnen-Dechent, W and Claesson-Welsh, L (2009) Type 3 cystatins; fetuins, kininogen and histidine-rich glycoprotein. Frontiers in Bioscience (Landmark Ed) 14, 2911–2922.10.2741/3422CrossRefGoogle ScholarPubMed
Lejkina, ES (1965) Research on ascariasis immunity and immunodiagnosis. Bulletin of the World Health Organization 32, 699–708.Google ScholarPubMed
Lewis, R, Behnke, JM, Stafford, P and Holland, CV (2006) The development of a mouse model to explore resistance and susceptibility to early Ascaris suum infection. Parasitology 132, 289–300.10.1017/S0031182005008978CrossRefGoogle ScholarPubMed
Lin, X, Xu, Y, Xu, J, Pan, X, Song, X, Shan, L, Zhao, Y and Shan, PF (2020) Global burden of noncommunicable disease attributable to high body mass index in 195 countries and territories, 1990-2017. Endocrine 69, 310–320.10.1007/s12020-020-02352-yCrossRefGoogle ScholarPubMed
Lozano, A, Zakzuk, J, Mercado, D and Caraballo, L (2020) Modulation of T cell responses by a helminth immunomodulator from Ascaris lumbricoides. Allergy, 75 s109, 15–16.Google Scholar
Lynch, NR, Isturiz, G, Sanchez, Y, Perez, M, Martinez, A and Castes, M (1992) Bronchial challenge of tropical asthmatics with Ascaris lumbricoides. Journal of Investigational Allergology & Clinical Immunology 2, 97–105.Google ScholarPubMed
Maizels, RM (2016) Parasitic helminth infections and the control of human allergic and autoimmune disorders. Clinical Microbiology and Infection 22, 481–486.10.1016/j.cmi.2016.04.024CrossRefGoogle ScholarPubMed
Maizels, RM, Smits, HH and McSorley, HJ (2018) Modulation of host immunity by helminths: the expanding repertoire of parasite effector molecules. Immunity 49, 801–818.10.1016/j.immuni.2018.10.016CrossRefGoogle ScholarPubMed
Manoury, B, Gregory, WF, Maizels, RM and Watts, C (2001) Bm-CPI-2, a cystatin homolog secreted by the filarial parasite Brugia malayi, inhibits class II MHC-restricted antigen processing. Current Biology 11, 447–451.10.1016/S0960-9822(01)00118-XCrossRefGoogle ScholarPubMed
Margis, R, Reis, EM and Villeret, V (1998) Structural and phylogenetic relationships among plant and animal cystatins. Archives of Biochemistry and Biophysics 359, 24–30.10.1006/abbi.1998.0875CrossRefGoogle ScholarPubMed
Martins, LA, Kotal, J, Bensaoud, C, Chmelar, J and Kotsyfakis, M (2020) Small protease inhibitors in tick saliva and salivary glands and their role in tick-host-pathogen interactions. Biochimica et Biophysica Acta Proteins Proteomics 1868, 140336.10.1016/j.bbapap.2019.140336CrossRefGoogle ScholarPubMed
Masure, D, Vlaminck, J, Wang, T, Chiers, K, Van den Broeck, W, Vercruysse, J and Geldhof, P (2013a) A role for eosinophils in the intestinal immunity against infective Ascaris suum larvae. PLoS Neglected Tropical Diseases 7, e2138.10.1371/journal.pntd.0002138CrossRefGoogle Scholar
Masure, D, Wang, T, Vlaminck, J, Claerhoudt, S, Chiers, K, Van den Broeck, W, Saunders, J, Vercruysse, J and Geldhof, P (2013b). the intestinal expulsion of the roundworm Ascaris suum is associated with eosinophils, intra-epithelial T cells and decreased intestinal transit time. PLoS Neglected Tropical Diseases, 7, e2588.10.1371/journal.pntd.0002588CrossRefGoogle Scholar
McSharry, C, Xia, Y, Holland, CV and Kennedy, MW (1999) Natural immunity to Ascaris lumbricoides associated with immunoglobulin E antibody to ABA-1 allergen and inflammation indicators in children. Infection and Immunity 67, 484–489.10.1128/IAI.67.2.484-489.1999CrossRefGoogle ScholarPubMed
Medeiros, D, Silva, AR, Rizzo, JA, Motta, ME, Oliveira, FH and Sarinho, ES (2006) Total IgE level in respiratory allergy: study of patients at high risk for helminthic infection. Jornal de Pediatria 82, 255–259.10.2223/JPED.1503CrossRefGoogle ScholarPubMed
Mei, G, Dong, J, Li, Z, Liu, S, Liu, Y, Sun, M, Liu, G, Su, Z and Liu, J (2014) Structural basis for the immunomodulatory function of cysteine protease inhibitor from human roundworm Ascaris lumbricoides. PLoS ONE 9, e96069.10.1371/journal.pone.0096069CrossRefGoogle ScholarPubMed
Midttun, HLE, Acevedo, N, Skallerup, P, Almeida, S, Skovgaard, K, Andresen, L, Skov, S, Caraballo, L, van Die, I, Jorgensen, CB, Fredholm, M, Thamsborg, SM, Nejsum, P and Williams, AR (2018) Ascaris suum infection downregulates inflammatory pathways in the pig intestine in vivo and in human dendritic cells in vitro. Journal of Infectious Diseases 217, 310–319.10.1093/infdis/jix585CrossRefGoogle ScholarPubMed
Miquel, N, Roepstorff, A, Bailey, M and Eriksen, L (2005) Host immune reactions and worm kinetics during the expulsion of Ascaris suum in pigs. Parasite Immunology 27, 79–88.10.1111/j.1365-3024.2005.00752.xCrossRefGoogle ScholarPubMed
Morimoto, M, Zarlenga, D, Beard, H, Alkharouf, N, Matthews, BF and Urban, JF (2003) Ascaris suum: cDNA microarray analysis of 4th stage larvae (L4) during self-cure from the intestine. Experimental Parasitology 104, 113–121.10.1016/S0014-4894(03)00139-5CrossRefGoogle ScholarPubMed
Muller-Esterl, W, Fritz, H, Kellermann, J, Lottspeich, F, Machleidt, W and Turk, V (1985) Genealogy of mammalian cysteine proteinase inhibitors. Common evolutionary origin of stefins, cystatins and kininogens. FEBS Letters 191, 221–226.10.1016/0014-5793(85)80012-0CrossRefGoogle ScholarPubMed
Murray, J, Manoury, B, Balic, A, Watts, C and Maizels, R (2005) Bm-CPI-2, a cystatin from Brugia malayi nematode parasites, differs from Caenorhabditis elegans cystatins in a specific site mediating inhibition of the antigen-processing enzyme AEP. Molecular & Biochemical Parasitology 139, 197–203.10.1016/j.molbiopara.2004.11.008CrossRefGoogle Scholar
O'Toole, J, Mikulic, L and Kaminsky, DA (2016) Epidemiology and pulmonary physiology of severe asthma. Immunology and Allergy Clinics of North America 36, 425–438.10.1016/j.iac.2016.03.001CrossRefGoogle ScholarPubMed
Platts-Mills, TA (2015) The allergy epidemics: 1870–2010. Journal of Allergy and Clinical Immunology 136, 3–13.10.1016/j.jaci.2015.03.048CrossRefGoogle ScholarPubMed
Pullan, RL, Smith, JL, Jasrasaria, R and Brooker, SJ (2014) Global numbers of infection and disease burden of soil transmitted helminth infections in 2010. Parasites & Vectors 7, 37.10.1186/1756-3305-7-37CrossRefGoogle ScholarPubMed
Rawlings, ND and Barrett, AJ (1990) Evolution of proteins of the cystatin superfamily. Journal of Molecular Evolution 30, 60–71.10.1007/BF02102453CrossRefGoogle ScholarPubMed
Rawlings, ND and Bateman, A (2021) How to use the MEROPS database and website to help understand peptidase specificity. Protein Science 30, 83–92.10.1002/pro.3948CrossRefGoogle ScholarPubMed
Rawlings, ND, Tolle, DP and Barrett, AJ (2004) Evolutionary families of peptidase inhibitors. Biochemical Journal 378, 705–716.10.1042/bj20031825CrossRefGoogle ScholarPubMed
Rawlings, ND, Waller, M, Barrett, AJ and Bateman, A (2014) MEROPS: the database of proteolytic enzymes, their substrates and inhibitors. Nucleic Acids Research 42, D503–D509.10.1093/nar/gkt953CrossRefGoogle ScholarPubMed
Reina Ortiz, M, Schreiber, F, Benitez, S, Broncano, N, Chico, ME, Vaca, M, Alexander, N, Lewis, DJ, Dougan, G and Cooper, PJ (2011) Effects of chronic ascariasis and trichuriasis on cytokine production and gene expression in human blood: a cross-sectional study. PLoS Neglected Tropical Diseases 5, e1157.10.1371/journal.pntd.0001157CrossRefGoogle ScholarPubMed
Rocha, FA, Leite, AK, Pompeu, MM, Cunha, TM, Verri, WA Jr, Soares, FM, Castro, RR and Cunha, FQ (2008). Protective effect of an extract from Ascaris suum in experimental arthritis models. Infection and Immunity, 76, 2736–2745.10.1128/IAI.01085-07CrossRefGoogle ScholarPubMed
Rodriguez-Mahillo, AI, Gonzalez-Muñoz, M, Gomez-Aguado, F, Rodriguez-Perez, R, Corcuera, MT, Caballero, ML and Moneo, I (2007) Cloning and characterisation of the Anisakis simplex allergen Ani s 4 as a cysteine-protease inhibitor. International Journal for Parasitology 37, 907–917.10.1016/j.ijpara.2007.01.007CrossRefGoogle Scholar
Rosa, BA, Jasmer, DP and Mitreva, M (2014) Genome-wide tissue-specific gene expression, co-expression and regulation of co-expressed genes in adult nematode Ascaris suum. PLoS Neglected Tropical Diseases 8, e2678.10.1371/journal.pntd.0002678CrossRefGoogle ScholarPubMed
Roth-Walter, F, Adcock, IM, Benito-Villalvilla, C, Bianchini, R, Bjermer, L, Boyman, O, Caramori, G, Cari, L, Chung, KF, Diamant, Z, Eguiluz-Gracia, I, Knol, EF, Kolios, A, Levi-Schaffer, F, Nocentini, G, Palomares, O, Redegeld, F, Van Esch, B and Stellato, C (2020) Immune modulation via T regulatory cell enhancement: disease-modifying therapies for autoimmunity and their potential for chronic allergic and inflammatory diseases – an EAACI position paper of the Task Force on Immunopharmacology (TIPCO). Allergy. doi: 10.1111/all.14478.CrossRefGoogle Scholar
Salgame, P, Yap, GS and Gause, WC (2013) Effect of helminth-induced immunity on infections with microbial pathogens. Nature Immunology 14, 1118–1126.10.1038/ni.2736CrossRefGoogle ScholarPubMed
Saraiva, M and O'Garra, A (2010) The regulation of IL-10 production by immune cells. Nature Reviews Immunology 10, 170–181.10.1038/nri2711CrossRefGoogle ScholarPubMed
Schnoeller, C, Rausch, S, Pillai, S, Avagyan, A, Wittig, BM, Loddenkemper, C, Hamann, A, Hamelmann, E, Lucius, R and Hartmann, S (2008) A helminth immunomodulator reduces allergic and inflammatory responses by induction of IL-10-producing macrophages. Journal of Immunology 180, 4265–4272.10.4049/jimmunol.180.6.4265CrossRefGoogle ScholarPubMed
Schonemeyer, A, Lucius, R, Sonnenburg, B, Brattig, N, Sabat, R, Schilling, K, Bradley, J and Hartmann, S (2001) Modulation of human T cell responses and macrophage functions by onchocystatin, a secreted protein of the filarial nematode Onchocerca volvulus. Journal of Immunology 167, 3207–3215.10.4049/jimmunol.167.6.3207CrossRefGoogle Scholar
Serrano, FJ, Reina, D, Frontera, E, Roepstorff, A and Navarrete, I (2001) Resistance against migrating Ascaris suum larvae in pigs immunized with infective eggs or adult worm antigens. Parasitology 122, 699–707.10.1017/S0031182001007806CrossRefGoogle ScholarPubMed
Shamsi, A and Bano, B (2017) Journey of cystatins from being mere thiol protease inhibitors to at heart of many pathological conditions. International Journal of Biological Macromolecules 102, 674–693.10.1016/j.ijbiomac.2017.04.071CrossRefGoogle Scholar
Sun, Y, Liu, G, Li, Z, Chen, Y, Liu, Y, Liu, B and Su, Z (2013) Modulation of dendritic cell function and immune response by cysteine protease inhibitor from murine nematode parasite Heligmosomoides polygyrus. Immunology 138, 370–381.10.1111/imm.12049CrossRefGoogle ScholarPubMed
Titz, TO, de Araujo, CAA, Enobe, CS, Rigato, PO, Oshiro, TM and de Macedo-Soares, MF (2017) Ascaris suum infection modulates inflammation: implication of CD4(+) CD25(high) Foxp3(+) T cells and IL-10. Parasite Immunology 39, e12453.10.1111/pim.12453CrossRefGoogle ScholarPubMed
Togre, N, Bhoj, P, Goswami, K, Tarnekar, A, Patil, M and Shende, M (2018) Human filarial proteins attenuate chronic colitis in an experimental mouse model. Parasite Immunology 40, e12511.10.1111/pim.12511CrossRefGoogle Scholar
Turk, V and Bode, W (1991) The cystatins: protein inhibitors of cysteine proteinases. FEBS Letters 285, 213–219.10.1016/0014-5793(91)80804-CCrossRefGoogle ScholarPubMed
Turk, V, Stoka, V and Turk, D (2008) Cystatins: biochemical and structural properties, and medical relevance. Frontiers in Bioscience 13, 5406–5420.10.2741/3089CrossRefGoogle ScholarPubMed
Turner, JD, Faulkner, H, Kamgno, J, Kennedy, MW, Behnke, J, Boussinesq, M and Bradley, JE (2005) Allergen-specific IgE and IgG4 are markers of resistance and susceptibility in a human intestinal nematode infection. Microbes and Infection 7, 990–996.10.1016/j.micinf.2005.03.036CrossRefGoogle Scholar
van Riet, E, Wuhrer, M, Wahyuni, S, Retra, K, Deelder, AM, Tielens, AG, van der Kleij, D and Yazdanbakhsh, M (2006) Antibody responses to Ascaris-derived proteins and glycolipids: the role of phosphorylcholine. Parasite Immunology 28, 363–371.10.1111/j.1365-3024.2006.00844.xCrossRefGoogle ScholarPubMed
Venugopal, G, Mueller, M, Hartmann, S and Steinfelder, S (2017) Differential immunomodulation in human monocytes versus macrophages by filarial cystatin. PLoS ONE 12, e0188138.10.1371/journal.pone.0188138CrossRefGoogle ScholarPubMed
Wang, J, Czech, B, Crunk, A, Wallace, A, Mitreva, M, Hannon, GJ and Davis, RE (2011) Deep small RNA sequencing from the nematode Ascaris reveals conservation, functional diversification, and novel developmental profiles. Genome Research 21, 1462–1477.10.1101/gr.121426.111CrossRefGoogle ScholarPubMed
Wang, S, Xie, Y, Yang, X, Wang, X, Yan, K, Zhong, Z, Wang, X, Xu, Y, Zhang, Y, Liu, F and Shen, J (2016) Therapeutic potential of recombinant cystatin from Schistosoma japonicum in TNBS-induced experimental colitis of mice. Parasites & Vectors 9, 6.10.1186/s13071-015-1288-1CrossRefGoogle ScholarPubMed
Wiedemann, M and Voehringer, D (2020) Immunomodulation and immune escape strategies of gastrointestinal helminths and schistosomes. Frontiers in Immunology 11, 572865.10.3389/fimmu.2020.572865CrossRefGoogle ScholarPubMed
Yang, X, Liu, J, Yue, Y, Chen, W, Song, M, Zhan, X and Wu, Z (2014) Cloning, expression and characterisation of a type II cystatin from Schistosoma japonicum, which could regulate macrophage activation. Parasitology Research 113, 3985–3992.10.1007/s00436-014-4064-9CrossRefGoogle ScholarPubMed
Zakeri, A, Hansen, EP, Andersen, SD, Williams, AR and Nejsum, P (2018) Immunomodulation by helminths: intracellular pathways and extracellular vesicles. Frontiers in Immunology 9, 2349.10.3389/fimmu.2018.02349CrossRefGoogle ScholarPubMed
Zakzuk, J, Casadiego, S, Mercado, A, Alvis-Guzman, N and Caraballo, L (2018) Ascaris lumbricoides infection induces both, reduction and increase of asthma symptoms in a rural community. Acta Tropica 187, 1–4.10.1016/j.actatropica.2018.07.016CrossRefGoogle Scholar
Ziegler, T, Rausch, S, Steinfelder, S, Klotz, C, Hepworth, MR, Kuhl, AA, Burda, PC, Lucius, R and Hartmann, S (2015) A novel regulatory macrophage induced by a helminth molecule instructs IL-10 in CD4 + T cells and protects against mucosal inflammation. Journal of Immunology 194, 1555–1564.10.4049/jimmunol.1401217CrossRefGoogle ScholarPubMed
Zwicky, P, Unger, S and Becher, B (2020) Targeting interleukin-17 in chronic inflammatory disease: a clinical perspective. Journal of Experimental Medicine 217, e20191123.10.1084/jem.20191123CrossRefGoogle ScholarPubMed