Anti-inflammatory Potentials of Excretory/Secretory (ES) and Somatic Products of Marshallagia marshalli on Allergic Airway Inflammation in BALB/c Mice

  • Sima PARANDE SHIRVAN Dept. of Pathobiology, Faculty of Veterinary Medicine, Ferdowsi University of Mashhad, Mashhad, Iran
  • Hassan BORJI Dept. of Pathobiology, Faculty of Veterinary Medicine, Ferdowsi University of Mashhad, Mashhad, Iran
  • Ahmadreza MOVASSAGHI Dept. of Pathobiology, Faculty of Veterinary Medicine, Ferdowsi University of Mashhad, Mashhad, Iran
  • Mohammadreza KHAKZAD Zakaria Research Center, Faculty of Medicine, Islamic Azad University, Mashhad Branch, Mashhad, Iran
  • Hamidreza FARZIN Razi Vaccine and Serum Research Institute, Mashhad, Iran
  • Mohsen MALEKI Dept. of Pathobiology, Faculty of Veterinary Medicine, Ferdowsi University of Mashhad, Mashhad, Iran
  • Alireza HAGHPARAST Mail Dept. of Pathobiology, Faculty of Veterinary Medicine, Ferdowsi University of Mashhad, Mashhad, Iran
Asthma, Excretory/secretory, Helminth therapy, Marshallagia marshalli


Background: Inverse relationship between helminths infection and immune-mediated diseases has inspired researchers to investigate therapeutic potential of helminths in allergic asthma. Helminth unique ability to induce immunoregulatory responses has already been documented in several experimental studies. This study was designed to investigate whether excretory/secretory (ES) and somatic products of Marshallagia marshalli modulate the development of ovalbumin-induced airway inflammation in a mouse model.

Methods: This study was carried out at the laboratories of Immunology and Parasitology of Faculty of Veterinary Medicine, Ferdowsi University of Mashhad, Mashhad, Iran during spring and summer 2015. Allergic airway inflammation was induced in mice by intraperitoneal (IP) injection with ovalbumin (OVA). The effects of ES and somatic products of M. marshalli were analyzed by inflammatory cell infiltration in bronchoalveolar lavage fluid (BALF), pathological changes and IgE response.

Results: Treatment with ES and somatic products of M. marshalli decreased cellular infiltration into BALF when they were administered during sensitization with allergen. Pathological changes were decreased in helminth-treated group, as demonstrated by reduced inflammatory cell infiltration, goblet cell hyperplasia, epithelial lesion and smooth muscle hypertrophy. However, no significant differences were observed in IgE serum levels, cytokines and eosinophil counts between different groups.

Conclusion: This study provides new insights into anti-inflammatory effects of ES and somatic products of M. marshalli, during the development of non-eosinophilic model of asthma. Further study is necessary to characterize immunomodulatory molecules derived from M. marshalli as a candidate for the treatment of airway inflammation.


Lloyd CM, Hessel EM. Functions of T cells in asthma: more than just TH2 cells. Nat Rev Immunol. 2010;10(12):838-48.

Wenzel SE. Asthma phenotypes: the evolution from clinical to molecular approaches. Nat Med. 2012;18(5):716-25.

Ober C, Yao TC. The genetics of asthma and allergic disease: a 21st century perspective. Immunol Rev. 2011;242(1):10-30.

Wolterink RGK, Hendriks RW. Type 2 innate lymphocytes in allergic airway inflammation. Curr Allergy Asthma Rep. 2013;13(3):271-80.

Kondrashova A, Seiskari T, Ilonen J, Knip M, Hyöty H. The ‘Hygiene hypothesis’ and the sharp gradient in the incidence of autoimmune and allergic diseases between Russian Karelia and Finland. Apmis. 2013;121(6):478-93.

Bisgaard H, Bønnelykke K, Stokholm J. Immune‐mediated diseases and microbial exposure in early life. Clinical & Experimental Allergy. 2014;44(4):475-81.

Kramer A, Bekeschus S, Bröker B, Schleibinger H, Razavi B, Assadian O. Maintaining health by balancing microbial exposure and prevention of infection: the hygiene hypothesis versus the hypothesis of early immune challenge. J Hosp Infect. 2013;83:S29-S34.

Fleming J. Helminth therapy and multiple sclerosis. Int J Parasitol. 2013;43(3):259-74.

Correale J, Farez MF. Parasite Infections in Multiple Sclerosis Modulate Immune Responses through a Retinoic Acid–Dependent Pathway. The JI. 2013;191(7):3827-37.

Lu N, Wang L, Cao H, Liu L, Van Kaer L, Washington MK, et al. Activation of the Epidermal Growth Factor Receptor in Macrophages Regulates Cytokine Production and Experimental Colitis. The JI. 2014;192(3):1013-23.

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.

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(4):491-500.

Smith P, Mangan NE, Walsh CM, Fallon RE, McKenzie AN, van Rooijen N, et al. Infection with a helminth parasite prevents experimental colitis via a macrophage-mediated mechanism. The JI. 2007;178(7):4557-66.

Zaccone P, Cooke A. Helminth mediated modulation of Type 1 diabetes (T1D). Int J Parasitol. 2013;43(3):311-8.

Mishra P, Patel N, Wu W, Bleich D, Gause W. Prevention of type 1 diabetes through infection with an intestinal nematode parasite requires IL-10 in the absence of a Th2-type response. Mucosal Immunol. 2012;6(2):297-308.

Lund ME, O'Brien BA, Hutchinson AT, Robinson MW, Simpson AM, Dalton JP, et al. Secreted Proteins from the Helminth Fasciola hepatica Inhibit the Initiation of Autoreactive T Cell Responses and Prevent Diabetes in the NOD Mouse. PloS One. 2014;9(1):e86289.

Hamid F, Wiria AE, Wammes LJ, Kaisar MM, Lell B, Ariawan I, et al. A longitudinal study of allergy and intestinal helminth infections in semi urban and rural areas of Flores, Indonesia (ImmunoSPIN Study). BMC Infect Dis. 2011;11(1):83.

Kim SE, Kim J-H, Min B-H, Bae YM, Hong S-T, Choi M-H. Crude Extracts of Caenorhabditis elegans Suppress Airway Inflammation in a Murine Model of Allergic Asthma. PLoS One. 2012;7(4):e35447.

Schabussova I, Ul-Haq O, Hoflehner E, Akgün J, Wagner A, Loupal G, et al. Oesophagostomum dentatum Extract Modulates T Cell-Dependent Immune Responses to Bystander Antigens and Prevents the Development of Allergy in Mice. PloS One. 2013;8(7):e67544.

Ebner F, Hepworth M, Rausch S, Janek K, Niewienda A, Kühl A, et al. Therapeutic potential of larval excretory/secretory proteins of the pig whipworm Trichuris suis in allergic disease. Allergy. 2014;69(11):1489-97.

Lloyd CM, Hawrylowicz CM. Regulatory T cells in asthma. Immunity. 2009;31(3):438-49.

Harnett W, Harnett MM. Helminth-derived immunomodulators: can understanding the worm produce the pill?. Nat Rev Immunol. 2010;10(4):278-84.

Weinstock JV. Autoimmunity: The worm returns. Nature. 2012;491(7423):183-5.

McSorley HJ, Maizels RM. Helminth infections and host immune regulation. Clin Microbiol Rev. 2012;25(4):585-608.

Allen JE, Maizels RM. Diversity and dialogue in immunity to helminths. Nat Rev Immunol. 2011;11(6):375-88.

Grencis R. Immunity to Helminths: Resistance, Regulation, and Susceptibility to Gastrointestinal Nematodes. Annu Rev Immunol. 2014.

Taylor MD, van der Werf N, Maizels RM. T cells in helminth infection: the regulators and the regulated. Trends Immunol. 2012;33(4):181-9.

Hussaarts L, van der Vlugt LE, Yazdanbakhsh M, Smits HH. Regulatory B-cell induction by helminths: implications for allergic disease. J Allergy Clin Immunol. 2011;128(4):733-9.

Fleming J, Isaak A, Lee J, Luzzio C, Carrithers M, Cook T, et al. Probiotic helminth administration in relapsing–remitting multiple sclerosis: a phase 1 study. Multiple Sclerosis Journal. 2011;17(6):743-54.

Rosche B, Wernecke K-D, Ohlraun S, Dörr J-M, Paul F. Trichuris suis ova in relapsing-remitting multiple sclerosis and clinically isolated syndrome (TRIOMS): study protocol for a randomized controlled trial. Trials. 2013;14(1):112.

Sandborn W, Elliott D, Weinstock J, Summers R, Landry‐Wheeler A, Silver N, et al. Randomised clinical trial: the safety and tolerability of Trichuris suis ova in patients with Crohn's disease. Aliment Pharmacol Ther. 2013;38(3):255-63.

Yatsuda AP, Krijgsveld J, Cornelissen AW, Heck AJ, de Vries E. Comprehensive analysis of the secreted proteins of the parasite Haemonchus contortus reveals extensive sequence variation and differential immune recognition. J Biol Chem. 2003;278(19):16941-51.

Bergstrom R. Prevalence of Marshallagia marshalli (Oriov, 1933) in wild ruminants in Wyoming. Proc 0Ida Acad Sci. 1915;55:101-2.

Moradpour N, Borji H, Razmi G, Maleki M, Kazemi H. Pathophysiology of Marshallagia marshalli in experimentally infected lambs. Parasitology. 2013;140(14):1762-7.

Nabavi R, Eslami A, Shokrani H, Bokaie S, Shayan P, Saadati D. Study on the prevalence, intensity and seasonal dynamics of abomasal helminths in sheep from different climatic zones of Iran. World Appl Sci J. 2011;12:441-5.

Khakzad MR, Mirsadraee M, Mohammadpour A, Ghafarzadegan K, Hadi R, Saghari M, et al. Effect of verapamil on bronchial goblet cells of asthma: An experimental study on sensitized animals. Pulm Pharmacol Ther. 2012;25(2):163-8.

Bayne LJ, Vonderheide RH. Multicolor Flow Cytometric Analysis of Immune Cell Subsets in Tumor-Bearing Mice. Cold Spring Harb Protocls. 2013;2013(10):pdb. prot077198.

Helmby H. Human helminth therapy to treat inflammatory disorders-where do we stand? BMC Immunol. 2015;16(1):12.

Cheng AM, Jaint D, Thomas S, Wilson J, Parker W. Overcoming evolutionary mismatch by self-treatment with helminths: current practices and experience. JJEM. 2015.

Oh M-J, Paeng J-W, Lee J-Y, Lee B-J, Choi D-C. The effect of lipopolysaccharide-contaminated ovalbumin on airway inflammation and remodeling in a chronic murine asthma model. Eur Respir J. 2013;42(Suppl 57):P1580.

Gerhold K, Blümchen K, Bock A, Seib C, Stock P, Kallinich T, et al. Endotoxins prevent murine IgE production, TH2 immune responses, and development of airway eosinophilia but not airway hyperreactivity. J Allergy Clin Immunol. 2002;110(1):110-6.

Hogan SP, Matthaei KI, Young JM, Koskinen A, Young IG, Foster PS. A novel T cell-regulated mechanism modulating allergen-induced airways hyperreactivity in BALB/c mice independently of IL-4 and IL-5. J Immunol. 1998;161(3):1501-9.

Kitagaki K, Businga TR, Racila D, Elliott DE, Weinstock JV, Kline JN. Intestinal helminths protect in a murine model of asthma. J Immunol. 2006;177(3):1628-35.

Mawla MMA, Khalifa KE, Sammour SA, Nazeer JT. Evaluation of the suppressive

effects of Ascaris Pseudo‐Coelomic Fluid (PCF), Fasciola Excretory/Secretory Antigen

(FES) and Hydatid Antigen‐B (HAgB) on the development of experimental murine

asthma. PUJ. 2012;5(1):41‐48.

Wohlleben G, Trujillo C, Müller J, Ritze Y, Grunewald S, Tatsch U, et al. Helminth infection modulates the development of allergen‐induced airway inflammation. ‎Int Immunol. 2004;16(4):585-96.

Chu DK, Al-Garawi A, Llop-Guevara A, Pillai RA, Radford K, Shen P, et al. Therapeutic potential of anti-IL-6 therapies for granulocytic airway inflammation in asthma. Allergy Asthma Clin Immunol. 2015;11(1):14.

Chung HL. Asthma in childhood: a complex, heterogeneous disease. Korean J Pediatr. 2011;54(1):1-5.

Kurowska-Stolarska M, Kewin P, Murphy G, Russo RC, Stolarski B, Garcia CC, et al. IL-33 induces antigen-specific IL-5+ T cells and promotes allergic-induced airway inflammation independent of IL-4. J Immunol. 2008;181(7):4780-90.

Guo L, Huang Y, Chen X, Hu-Li J, Urban Jr JF, Paul WE. Innate immunological function of TH2 cells in vivo. Nature Immunol. 2015;16(10):1051-9.

Smits HH, Everts B, Hartgers FC, Yazdanbakhsh M. Chronic helminth infections protect against allergic diseases by active regulatory processes. Curr Allergy Asthma Rep. 2010;10(1):3-12.

Berry M, Morgan A, Shaw DE, Parker D, Green R, Brightling C, et al. Pathological features and inhaled corticosteroid response of eosinophilic and non-eosinophilic asthma. Thorax. 2007;62(12):1043-9.

Busse WW, Morgan WJ, Gergen PJ, Mitchell HE, Gern JE, Liu AH, et al. Randomized trial of omalizumab (anti-IgE) for asthma in inner-city children. N Engl J Med 2011;364(11):1005-15.

How to Cite
PARANDE SHIRVAN S, BORJI H, MOVASSAGHI A, KHAKZAD M, FARZIN H, MALEKI M, HAGHPARAST A. Anti-inflammatory Potentials of Excretory/Secretory (ES) and Somatic Products of Marshallagia marshalli on Allergic Airway Inflammation in BALB/c Mice. Iran J Parasitol. 11(4):515-526.
Original Article(s)