Immune modulation by helminth parasites is instrumental in their success, blocking protective immunity to ensure their survival. Immunomodulation also “spills over” to impact many other immune responses to “bystander” antigens that may otherwise be the targets of allergic reactions (to environmental substances), autoimmune diseases (to self antigens), and inflammatory bowel disease (to commensal bacteria).
Among the most intensively studied helminth immunomodulation models, is H. polygyrus. As far back as 2011 an extensive list was compiled as below:
| Antigen-specific responses | |
| Antibody to SRBC inhibited in infection | (Ali and Behnke, 1983; Ali and Behnke, 1984; Shimp et al., 1975) |
| Antibody to SRBC inhibited by adult worm homogenate, and by cells from mice given adult worm homogenate | (Pritchard et al., 1984) |
| Antibody to ovalbumin | (Boitelle et al., 2005) |
| Immune cell functions | |
| Inhibition of DC responses to TLR ligation, and reduction of IL-12 secretion | (Massacand et al., 2009; Segura et al., 2007) |
| Expansion of Foxp3+ CD103+ Tregs | (Finney et al., 2007; Rausch et al., 2008) |
| Induction of bystander (OVA-specific) Foxp3+ Tregs | (Grainger et al., 2010) |
| Autoimmunity | |
| Inhibits colitis in IL-10-deficient mice | (Elliott et al., 2004; Hang et al., 2010) |
| Inhibits TNBS-induced colitis | (Sutton et al., 2008) |
| Inhibits Type I diabetes | (Liu et al., 2009; Saunders et al., 2006) |
| Allergy | |
| Inhibits airway allergic inflammation | (Kitagaki et al., 2006; Wilson et al., 2005) |
| Inhibits food allergy | (Bashir et al., 2002) |
| Co-infections | |
| Reduces liver immunopathological reactions to schistosome eggs | (Bazzone et al., 2008) |
| Exacerbates Plasmodium chabaudi and P. yoelii infections, suppressing IFN-γ responses | (Helmby, 2009; Noland et al., 2008; Su et al., 2005; Tetsutani et al., 2009) |
| Aggravates Citrobacter rodentium infection and colitis | (Chen et al., 2005; Weng et al., 2007) |
| Extends Nippostrongylus brasiliensis, Trichuris muris and Trichinella spiralis infections, suppresses IL-9 and mast cell response | (Behnke et al., 1978; Behnke et al., 1993; Colwell and Wescott, 1973; Dehlawi et al., 1987; Jenkins and Behnke, 1977) |
| Modulates Helicobacter pylori-induced inflammation | (Fox et al., 2000) |
| Results in greater Eimeria facliformis proliferation | (Rausch et al., 2010) |
| Inhibits protective CD8+ T cell responses to Toxoplasma gondii | (Khan et al., 2008) |
| Reduced antibody responses to haemagglutinin in influenza A infections | (Chowaniec et al., 1972) |
| Reduces response to malaria and Salmonella vaccination | (Druilhe et al., 2006; Su et al., 2006; Urban et al., 2007) |
References
Ali, N.M., Behnke, J.M., 1983, Nematospiroides dubius: factors affecting the primary response to SRBC in infected mice. J Helminthol57, 343-353.
Ali, N.M.H., Behnke, J.M., 1984, Non-specific immunodepression by larval and adult Nematospiroides dubius. Parasitology88, 153-162.
Bashir, M.E., Andersen, P., Fuss, I.J., Shi, H.N., Nagler-Anderson, C., 2002, An enteric helminth infection protects against an allergic response to dietary antigen. J Immunol169, 3284-3292.
Bazzone, L.E., Smith, P.M., Rutitzky, L.I., Shainheit, M.G., Urban, J.F., Setiawan, T., Blum, A.M., Weinstock, J.V., Stadecker, M.J., 2008, Coinfection with the intestinal nematode Heligmosomoides polygyrus markedly reduces hepatic egg-induced immunopathology and proinflammatory cytokines in mouse models of severe schistosomiasis. Infect Immun76, 5164-5172.
Behnke, J.M., Wakelin, D., Wilson, M.M., 1978, Trichinella spiralis: delayed rejection in mice concurrently infected with Nematospiroides dubius. Exp Parasitol46, 121-130.
Behnke, J.M., Wahid, F.N., Grencis, R.K., Else, K.J., Ben-Smith, A.W., Goyal, P.K., 1993, Immunological relationships during primary infection with Heligmosomoides polygyrus (Nematospiroides dubius ): downregulation of specific cytokine secretion (IL-9 and IL-10) correlates with poor mastocytosis and chronic survival of adult worms. Parasite Immunology15, 415-421.
Boitelle, A., Di Lorenzo, C., Scales, H.E., Devaney, E., Kennedy, M.W., Garside, P., Lawrence, C.E., 2005, Contrasting effects of acute and chronic gastro-intestinal helminth infections on a heterologous immune response in a transgenic adoptive transfer model. Int J Parasitol35, 765-775.
Chen, C.C., Louie, S., McCormick, B., Walker, W.A., Shi, H.N., 2005, Concurrent infection with an intestinal helminth parasite impairs host resistance to enteric Citrobacter rodentium and enhances Citrobacter-induced colitis in mice. Infect Immun73, 5468-5481.
Chowaniec, W., Wescott, R.B., Congdon, L.L., 1972, Interaction of Nematospiroides dubius and influenza virus in mice. Experimental Parasitology32, 33-44.
Colwell, D.A., Wescott, R.B., 1973, Prolongation of egg production of Nippostrongylus brasiliensis in mice concurrently infected with Nematospiroides dubius. Journal of Parasitology59, 216.
Dehlawi, M.S., Wakelin, D., Behnke, J.M., 1987, Suppression of mucosal mastocytosis by infection with the intestinal nematode Nematospiroides dubius. Parasite Immunology9, 187-194.
Druilhe, P., Sauzet, J.P., Sylla, K., Roussilhon, C., 2006, Worms can alter T cell responses and induce regulatory T cells to experimental malaria vaccines. Vaccine24, 4902-4904.
Elliott, D.E., Setiawan, T., Metwali, A., Blum, A., Urban, J.F., Jr., Weinstock, J.V., 2004, Heligmosomoides polygyrus inhibits established colitis in IL-10-deficient mice. European Journal of Immunology34, 2690-2698.
Finney, C.A.M., Taylor, M.D., Wilson, M.S., Maizels, R.M., 2007, Expansion and activation of CD4+CD25+ regulatory T cells in Heligmosomoides polygyrus infection. European Journal of Immunology37, 1874-1886.
Fox, J.G., Beck, P., Dangler, C.A., Whary, M.T., Wang, T.C., Shi, H.N., Nagler-Anderson, C., 2000, Concurrent enteric helminth infection modulates inflammation and gastric immune responses and reduces Helicobacter-induced gastric atrophy. Nature Medicine6, 536-542.
Grainger, J.R., Smith, K.A., Hewitson, J.P., McSorley, H.J., Harcus, Y., Filbey, K.J., Finney, C.A.M., Greenwood, E.J.D., Knox, D.P., Wilson, M.S., Belkaid, Y., Rudensky, A.Y., Maizels, R.M., 2010, Helminth secretions induce de novo T cell Foxp3 expression and regulatory function through the TGF-β pathway. J Exp Med207, 2331-2341.
Hang, L., Setiawan, T., Blum, A.M., Urban, J., Stoyanoff, K., Arihiro, S., Reinecker, H.C., Weinstock, J.V., 2010, Heligmosomoides polygyrus infection can inhibit colitis through direct interaction with innate immunity. J Immunol185, 3184-3189.
Helmby, H., 2009, Gastrointestinal nematode infection exacerbates malaria-induced liver pathology. J Immunol182, 5663-5671.
Jenkins, S.N., Behnke, J.M., 1977, Impairment of primary expulsion of Trichuris muris in mice concurrently infected with Nematospiroides dubius. Parasitology75, 71-78.
Khan, I.A., Hakak, R., Eberle, K., Sayles, P., Weiss, L.M., Urban, J.F., Jr., 2008, Coinfection with Heligmosomoides polygyrus fails to establish CD8+ T-cell immunity against Toxoplasma gondii. Infect Immun76, 1305-1313.
Kitagaki, K., Businga, T.R., Racila, D., Elliott, D.E., Weinstock, J.V., Kline, J.N., 2006, Intestinal helminths protect in a murine model of asthma. J Immunol177, 1628-1635.
Liu, Q., Sundar, K., Mishra, P.K., Mousavi, G., Liu, Z., Gaydo, A., Alem, F., Lagunoff, D., Bleich, D., Gause, W.C., 2009, Helminth infection can reduce insulitis and type 1 diabetes through CD25- and IL-10-independent mechanisms. Infect Immun77, 5347-5358.
Massacand, J.C., Stettler, R.C., Meier, R., Humphreys, N.E., Grencis, R.K., Marsland, B.J., Harris, N.L., 2009, Helminth products bypass the need for TSLP in Th2 immune responses by directly modulating dendritic cell function. Proc Natl Acad Sci U S A106, 13968-13973.
Noland, G.S., Urban, J.F., Jr., Fried, B., Kumar, N., 2008, Counter-regulatory anti-parasite cytokine responses during concurrent Plasmodium yoelii and intestinal helminth infections in mice. Exp Parasitol119, 272-278.
Pritchard, D.I., Ali, N.M.H., Behnke, J.M., 1984, Analysis of the mechanism of immunodepression following heterologous antigenic stimulation during concurrent infection with Nematospiroides dubius. Immunology51, 633-642.
Rausch, S., Huehn, J., Kirchhoff, D., Rzepecka, J., Schnoeller, C., Pillai, S., Loddenkemper, C., Scheffold, A., Hamann, A., Lucius, R., Hartmann, S., 2008, Functional analysis of effector and regulatory T cells in a parasitic nematode infection. Infection and Immunity76, 1908-1919.
Rausch, S., Held, J., Stange, J., Lendner, M., Hepworth, M.R., Klotz, C., Lucius, R., Pogonka, T., Hartmann, S., 2010, A matter of timing: Early, not chronic phase intestinal nematode infection restrains control of a concurrent enteric protozoan infection. Eur J Immunol40, 2804-2815.
Saunders, K.A., Raine, T., Cooke, A., Lawrence, C.E., 2006, Inhibition of autoimmune type 1 diabetes by gastrointestinal helminth infection. Infect Immun75, 397-407.
Segura, M., Su, Z., Piccirillo, C., Stevenson, M.M., 2007, Impairment of dendritic cell function by excretory-secretory products: A potential mechanism for nematode-induced immunosuppression. Eur J Immunol37, 1887-1904.
Shimp, R.G., Crandall, R.B., Crandall, C.A., 1975, Heligmosomoides polygyrus (=Nematospiroides dubius ): suppression of antibody response to orally adminstered sheep erythrocytes in infected mice. Experimental Parasitology38, 257-269.
Su, Z., Segura, M., Morgan, K., Loredo-Osti, J.C., Stevenson, M.M., 2005, Impairment of protective immunity to blood-stage malaria by concurrent nematode infection. Infect Immun73, 3531-3539.
Su, Z., Segura, M., Stevenson, M.M., 2006, Reduced protective efficacy of a blood-stage malaria vaccine by concurrent nematode infection. Infect Immun74, 2138-2144.
Sutton, T.L., Zhao, A., Madden, K.B., Elfrey, J.E., Tuft, B.A., Sullivan, C.A., Urban, J.F., Jr., Shea-Donohue, T., 2008, Anti-Inflammatory mechanisms of enteric Heligmosomoides polygyrus infection against trinitrobenzene sulfonic acid-induced colitis in a murine model. Infect Immun76, 4772-4782.
Tetsutani, K., Ishiwata, K., Ishida, H., Tu, L., Torii, M., Hamano, S., Himeno, K., Hisaeda, H., 2009, Concurrent infection with Heligmosomoides polygyrus suppresses anti-Plasmodium yoelii protection partially by induction of CD4+CD25+Foxp3+ Treg in mice. Eur J Immunol39, 2822-2830.
Urban, J.F., Jr., Steenhard, N.R., Solano-Aguilar, G.I., Dawson, H.D., Iweala, O.I., Nagler, C.R., Noland, G.S., Kumar, N., Anthony, R.M., Shea-Donohue, T., Weinstock, J., Gause, W.C., 2007, Infection with parasitic nematodes confounds vaccination efficacy. Vet Parasitol148, 14-20.
Weng, M., Huntley, D., Huang, I.F., Foye-Jackson, O., Wang, L., Sarkissian, A., Zhou, Q., Walker, W.A., Cherayil, B.J., Shi, H.N., 2007, Alternatively activated macrophages in intestinal helminth infection: effects on concurrent bacterial colitis. J Immunol179, 4721-4731.
Wilson, M.S., Taylor, M., Balic, A., Finney, C.A.M., Lamb, J.R., Maizels, R.M., 2005, Suppression of allergic airway inflammation by helminth-induced regulatory T cells. Journal of Experimental Medicine202, 1199-1212.