Lower Expression of TLR2 and SOCS-3 Is Associated with Schistosoma haematobium Infection and with Lower Risk for Allergic Reactivity in Children Living in a Rural Area in Ghana
Background Helminth infections are prevalent in rural areas of developing countries and have in some studies been negatively associated with allergic disorders and atopy. In this context little is known of the molecular mechanisms of modulation involved. We have characterized the innate immune responses, at the molecular level, in children according to their helminth infection status and their atopic reactivity to allergens. Methodology/Principal Findings The mRNA expression of several genes of the innate immune system that have been associated with microbial exposure and allergy was examined in 120 school children in a rural area in Ghana. Helminth infections were common and atopy rare in the study area. The analysis of gene expression in ex vivo whole blood samples reflected the levels of corresponding proteins. Using this approach in a population of school children in whom the presence of Schistosoma haematobium infection was associated with protection from atopic reactivity, we found that the level of TLR2 and SOCS-3, genes associated with atopy in the children, were significantly downregulated by presence of S. haematobium infection. Conclusions S. haematobium infections modulate the expression of genes of the innate immune system (TLR2 and SOCS-3); these are genes that are associated with increased allergic inflammatory processes, providing a molecular link between the negative association of this infection and atopy in rural children in Ghana.
References
[1]
Maizels RM, Yazdanbakhsh M (2003) Immune regulation by helminth parasites: cellular and molecular mechanisms. Nat Rev Immunol 3: 733–744. doi: 10.1038/nri1183
[2]
Sabin EA, Araujo MI, Carvalho EM, Pearce EJ (1996) Impairment of tetanus toxoid-specific Th1-like immune responses in humans infected with Schistosoma mansoni. J Infect Dis 173: 269–272. doi: 10.1093/infdis/173.1.269
[3]
Cooper PJ, Espinel I, Paredes W, Guderian RH, Nutman TB (1998) Impaired tetanus-specific cellular and humoral responses following tetanus vaccination in human onchocerciasis: a possible role for interleukin-10. J Infect Dis 178: 1133–1138. doi: 10.1086/515661
[4]
Smits HH, Hartgers FC, Yazdanbakhsh M (2005) Helminth infections: Protection from atopic disorders. Current Allergy and Asthma Reports 5: 42–50. doi: 10.1007/s11882-005-0053-5
[5]
Flohr C, Tuyen LN, Lewis S, Quinnell R, Minh TT, Liem HT, Campbell J, Pritchard D, Hien TT, Farrar J, Williams HC, Britton J (2006) Poor sanitation and helminth infection protect against skin sensitization in Vietnamese children: A cross-sectional study. American Journal of Tropical Medicine and Hygiene 75: 321. doi: 10.1016/j.jaci.2006.08.035
[6]
Scrivener S, Yemaneberhan H, Zebenigus M, Tilahun D, Girma S, Ali S, McElroy P, Custovic A, Woodcock A, Pritchard D, Venn A, Britton J (2001) Independent effects of intestinal parasite infection and domestic allergen exposure on risk of wheeze in Ethiopia: a nested case-control study. Lancet 358: 1493–1499. doi: 10.1016/S0140-6736(01)06579-5
[7]
van Den Biggelaar AH, van Ree R, Rodrigues LC, Lell B, Deelder AM, Kremsner PG, Yazdanbakhsh M (2000) Decreased atopy in children infected with Schistosoma haematobium: a role for parasite-induced interleukin-10. Lancet 356: 1723–1727. doi: 10.1016/S0140-6736(00)03206-2
[8]
Araujo MI, Lopes AA, Medeiros M, Cruz AA, Sousa-Atta L, Sole D, Carvalho EM (2000) Inverse association between skin response to aeroallergens and Schistosoma mansoni infection. Int Arch Allergy Immunol 123: 145–148. doi: 24433
[9]
Lynch NR, Hagel I, Perez M, Di Prisco MC, Lopez R, Alvarez N (1993) Effect of anthelmintic treatment on the allergic reactivity of children in a tropical slum. J Allergy Clin Immunol 92: 404–411. doi: 10.1016/0091-6749(93)90119-Z
[10]
van Den Biggelaar AH, Rodrigues LC, van Ree R, van der Zee JS, Hoeksma-Kruize YC, Souverijn JH, Missinou MA, Borrmann S, Kremsner PG, Yazdanbakhsh M (2004) Long-term treatment of intestinal helminths increases mite skin-test reactivity in Gabonese schoolchildren. J Infect Dis 189: 892–900. doi: 10.1086/381767
[11]
Cooper PJ, Chico ME, Vaca MG, Moncayo AL, Bland JM, Mafla E, Sanchez F, Rodrigues LC, Strachan DP, Griffin GE (2006) Effect of albendazole treatments on the prevalence of atopy in children living in communities endemic for geohelminth parasites: a cluster-randomised trial. Lancet 367: 1598–1603. doi: 10.1016/S0140-6736(06)68697-2
[12]
Braun-Fahrlander C, Riedler J, Herz U, Eder W, Waser M, Grize L, Maisch S, Carr D, Gerlach F, Bufe A, Lauener RP, Schierl R, Renz H, Nowak D, von Mutius E (2002) Environmental exposure to endotoxin and its relation to asthma in school-age children. N Engl J Med 347: 869–877. doi: 10.1056/NEJMoa020057
[13]
Velasco G, Campo M, Manrique OJ, Bellou A, He H, Arestides RS, Schaub B, Perkins DL, Finn PW (2005) Toll-like receptor 4 or 2 agonists decrease allergic inflammation. Am J Respir Cell Mol Biol 32: 218–224. doi: 10.1165/rcmb.2003-0435OC
[14]
Eisenbarth SC, Piggott DA, Huleatt JW, Visintin I, Herrick CA, Bottomly K (2002) Lipopolysaccharide-enhanced, Toll-like Receptor 4-dependent T Helper Cell Type 2 Responses to Inhaled Antigen. J Exp Med 196: 1645–1651. doi: 10.1084/jem.20021340
[15]
Kane CM, Cervi L, Sun J, McKee AS, Masek KS, Shapira S, Hunter CA, Pearce EJ (2004) Helminth antigens modulate TLR-initiated dendritic cell activation. J Immunol 173: 7454–7461.
[16]
Lauener RP, Birchler T, Adamski J, Braun-Fahrlander C, Bufe A, Herz U, von Mutius E, Nowak D, Riedler J, Waser M, Sennhauser FH (2002) Expression of CD14 and Toll-like receptor 2 in farmers' and non-farmers' children. Lancet 360: 465–466. doi: 10.1016/S0140-6736(02)09641-1
[17]
Fujimoto M, Tsutsui H, Xinshou O, Tokumoto M, Watanabe D, Shima Y, Yoshimoto T, Hirakata H, Kawase I, Nakanishi K, Kishimoto T, Naka T (2004) Inadequate induction of suppressor of cytokine signaling-1 causes systemic autoimmune diseases. Int Immunol 16: 303–314. doi: 10.1093/intimm/dxh030
[18]
Marine JC, Topham DJ, McKay C, Wang D, Parganas E, Stravopodis D, Yoshimura A, Ihle JN (1999) SOCS1 deficiency causes a lymphocyte-dependent perinatal lethality. Cell 98: 609–616. doi: 10.1016/S0092-8674(00)80048-3
[19]
Naka T, Fujimoto M, Tsutsui H, Yoshimura A (2005) Negative regulation of cytokine and TLR signalings by SOCS and others. Adv Immunol 87: 61–122. doi: 10.1016/S0065-2776(05)87003-8
[20]
Mansell A, Smith R, Doyle SL, Gray P, Fenner JE, Crack PJ, Nicholson SE, Hilton DJ, O'Neill LA, Hertzog PJ (2006) Suppressor of cytokine signaling 1 negatively regulates Toll-like receptor signaling by mediating Mal degradation. Nat Immunol 7: 148–155. doi: 10.1038/ni1299
[21]
Suzuki A, Hanada T, Mitsuyama K, Yoshida T, Kamizono S, Hoshino T, Kubo M, Yamashita A, Okabe M, Takeda K, Akira S, Matsumoto S, Toyonaga A, Sata M, Yoshimura A (2001) CIS3/SOCS3/SSI3 plays a negative regulatory role in STAT3 activation and intestinal inflammation. J Exp Med 193: 471–481. doi: 10.1084/jem.193.4.471
[22]
Shouda T, Yoshida T, Hanada T, Wakioka T, Oishi M, Miyoshi K, Komiya S, Kosai K, Hanakawa Y, Hashimoto K, Nagata K, Yoshimura A (2001) Induction of the cytokine signal regulator SOCS3/CIS3 as a therapeutic strategy for treating inflammatory arthritis. J Clin Invest 108: 1781–1788. doi: 10.1172/JCI13568
[23]
Seki Y, Inoue H, Nagata N, Hayashi K, Fukuyama S, Matsumoto K, Komine O, Hamano S, Himeno K, Inagaki-Ohara K, Cacalano N, O'Garra A, Oshida T, Saito H, Johnston JA, Yoshimura A, Kubo M (2003) SOCS-3 regulates onset and maintenance of T(H)2-mediated allergic responses. Nat Med 9: 1047–1054. doi: 10.1038/nm896
[24]
Ozaki A, Seki Y, Fukushima A, Kubo M (2005) The control of allergic conjunctivitis by suppressor of cytokine signaling (SOCS)3 and SOCS5 in a murine model. J Immunol 175: 5489–5497.
[25]
Van der Kleij D, van Den Biggelaar AH, Kruize YC, Retra K, Fillie Y, Schmitz M, Kremsner PG, Tielens AG, Yazdanbakhsh M (2004) Responses to Toll-like receptor ligands in children living in areas where schistosome infections are endemic. J Infect Dis 189: 1044–1051. doi: 10.1086/382089
[26]
van Den Biggelaar AH, Lopuhaa C, van Ree R, van der Zee JS, Jans J, Hoek A, Migombet B, Borrmann S, Luckner D, Kremsner PG, Yazdanbakhsh M (2001) The prevalence of parasite infestation and house dust mite sensitization in Gabonese schoolchildren. Int Arch Allergy Immunol 126: 231–238. doi: 10.1159/000049519
[27]
Aalberse RC, Koshte V, Clemens JG (1981) Immunoglobulin E antibodies that crossreact with vegetable foods, pollen, and Hymenoptera venom. J Allergy Clin Immunol 68: 356–364. doi: 10.1016/0091-6749(81)90133-0
[28]
User Bulletin #2 (2005) ABI Prism 7700 Sequence Detection System. P/N 4303859 Rev. A, Stock No. 777802-001.
[29]
Amoudruz P, Holmlund U, Malmstrom V, Trollmo C, Bremme K, Scheynius A, Sverremark-Ekstrom E (2005) Neonatal immune responses to microbial stimuli: is there an influence of maternal allergy? J Allergy Clin Immunol 115: 1304–1310. doi: 10.1016/j.jaci.2005.02.036
[30]
Krauss-Etschmann S, Hartl D, Heinrich J, Thaqi A, Prell C, Campoy C, Molina FS, Hector A, Decsi T, Schendel DJ, Koletzko BV (2006) Association between levels of Toll-like receptors 2 and 4 and CD14 mRNA and allergy in pregnant women and their offspring. Clin Immunol 118: 292–299. doi: 10.1016/j.clim.2005.10.003
[31]
Babu S, Blauvelt CP, Kumaraswami V, Nutman TB (2006) Cutting Edge: Diminished T Cell TLR Expression and Function Modulates the Immune Response in Human Filarial Infection. J Immunol 176: 3885–3889.
[32]
Babu S, Blauvelt CP, Kumaraswami V, Nutman TB (2005) Diminished expression and function of TLR in lymphatic filariasis: a novel mechanism of immune dysregulation. J Immunol 175: 1170–1176.
[33]
Baetz A, Frey M, Heeg K, Dalpke AH (2004) Suppressor of cytokine signaling (SOCS) proteins indirectly regulate toll-like receptor signaling in innate immune cells. J Biol Chem 279: 54708–54715. doi: 10.1074/jbc.M410992200
[34]
Kinjyo I, Inoue H, Hamano S, Fukuyama S, Yoshimura T, Koga K, Takaki H, Himeno K, Takaesu G, Kobayashi T, Yoshimura A (2006) Loss of SOCS3 in T helper cells resulted in reduced immune responses and hyperproduction of interleukin 10 and transforming growth factor-beta1. J Exp Med 203: 1021–1031. doi: 10.1084/jem.20052333
[35]
Pillemer BBL, Xu H, Oriss TB, Qi Z, Ray A (2007) Deficient SOCS3 expression in CD4+CD25+FoxP3+ regulatory T cells and SOCS3-mediated suppression of Treg function. Eur J Immunol 37: 2082–2089. doi: 10.1002/eji.200737193
[36]
Platts-Mills T, Vaughan J, Squillace S, Woodfolk J, Sporik R (2001) Sensitisation, asthma, and a modified Th2 response in children exposed to cat allergen: a population-based cross-sectional study. Lancet 357: 752–756. doi: 10.1016/S0140-6736(00)04168-4
[37]
Maldonado C, Trejo W, Ramirez A, Carrera M, Sanchez J, Lopez-Macias C, Isibasi A (2000) Lipophosphopeptidoglycan of Entamoeba histolytica induces an antiinflammatory innate immune response and downregulation of toll-like receptor 2 (TLR-2) gene expression in human monocytes. Arch Med Res 31: S71–S73. doi: 10.1016/S0188-4409(00)00199-5
[38]
Brodskyn C, Patricio J, Oliveira R, Lobo L, Arnholdt A, Mendonca-Previato L, Barral A, Barral-Netto M (2002) Glycoinositolphospholipids from Trypanosoma cruzi interfere with macrophages and dendritic cell responses. Infect Immun 70: 3736–3743. doi: 10.1128/IAI.70.7.3736-3743.2002
[39]
Ropert C, Gazzinelli RT (2004) Regulatory role of Toll-like receptor 2 during infection with Trypanosoma cruzi. J Endotoxin Res 10: 425–430. doi: 10.1179/096805104225006507
[40]
Fan H, Cook JA (2004) Molecular mechanisms of endotoxin tolerance. J Endotoxin Res 10: 71–84. doi: 10.1179/096805104225003997
[41]
Bosisio D, Polentarutti N, Sironi M, Bernasconi S, Miyake K, Webb GR, Martin MU, Mantovani A, Muzio M (2002) Stimulation of toll-like receptor 4 expression in human mononuclear phagocytes by interferon-gamma: a molecular basis for priming and synergism with bacterial lipopolysaccharide. Blood 99: 3427–3431. doi: 10.1182/blood.V99.9.3427
[42]
Mita Y, Dobashi K, Endou K, Kawata T, Shimizu Y, Nakazawa T, Mori M (2002) Toll-like receptor 4 surface expression on human monocytes and B cells is modulated by IL-2 and IL-4. Immunol Lett 81: 71–75. doi: 10.1016/S0165-2478(01)00328-5
[43]
Mueller T, Terada T, Rosenberg IM, Shibolet O, Podolsky DK (2006) Th2 cytokines down-regulate TLR expression and function in human intestinal epithelial cells. J Immunol 176: 5805–5814.