Advertisement

Parasitology Research

, Volume 117, Issue 1, pp 115–126 | Cite as

Immune modulation of Th1, Th2, and T-reg transcriptional factors differing from cytokine levels in Schistosoma japonicum infection

  • Amel Farwa
  • Chao He
  • Longfei Xia
  • Hong ZhouEmail author
Original Paper

Abstract

In spite of long-term integrated control programs for Schistosoma japonicum infection in China, the infection is still persistent due to its zoonotic transmission and disease severity which further complicate its control. Th1, Th2, and T-reg cells are involved in S. japonicum immunity; however, their exact roles in immunopathology of this infection are still questionable. Therefore, the monitoring of these T cell subsets’ immune responses during a primary infection of S. japonicum at both transcriptional (mRNA) and protein (cytokines) levels would be essential to point out. In experimentally infected white New Zealand rabbits, mRNA expression levels of TBX2, IRF8, GATA3, STAT6, FoxP3, and MAFF were evaluated using qPCR, whereas Th1 (IFN-γ and TNF-α), Th2 (IL4 and IL13), and T-reg (IL10 and TGF-β1) cytokines were measured by ELISA test. Those parameters were estimated at two phases: the first being 4 and 8 weeks post-infection and the second phase at 12 weeks post-infection. The infected rabbits were categorized into group1 which was treated with praziquantel after the 8th week of infection and group 2 which was left untreated. In the first stage of infection, Th1 was superior to the other types at both mRNA (TBX2 and IRF8) and protein (IFN-γ and TNF-α) levels, but at the late stage, Th2 cytokines (IL4 and IL13) were surprisingly dominated without comparable change in Th2 transcriptional level in group 1. Concisely, the evaluation of T cell transcriptional factors provided clearer evidence about T cellular roles which would be a valuable supplement to control this disease in terms of protective and therapeutic vaccinations.

Keywords

S. japonicum Transcriptional factors FoxP3 IL4 

Notes

Acknowledgments

All experimental rabbits were provided by the Laboratory Animal Research Center of Jiangsu University. A great thanks to Yun Nan Center for Disease Control and Prevention which provided S. japonicum cercaria Chinese strains and the Zhenjiang Center for Disease Prevention and Control for supplementation of therapeutic praziquantel.

Funding information

This study was financially supported by National Natural Science Foundation of China (No. 81370614) to Hong Zhou.

Compliance with ethical standards

Ethics approval

All experimental rabbits in the Laboratory Animal Research Center of Jiangsu University were harbored, fed, and monitored during the whole period of the experiment according to Chinese animal protection laws. Blood sample collection and scarification procedures were performed under the supervision of a lab animal assistant in the center. Additionally, all applicable international, national, and/or institutional guidelines for the care and use of animals were followed.

Conflict of interests

The authors declare that they have no conflict of interest.

References

  1. Adalid-Peralta L, Fragoso G, Fleury A, Sciutto E (2011) Mechanisms underlying the induction of regulatory T cells and its relevance in the adaptive immune response in parasitic infections. Int J Biol Sci 7(9):1412–1426.  https://doi.org/10.7150/ijbs.7.1412 CrossRefPubMedPubMedCentralGoogle Scholar
  2. Boamah D, Kikuchi M, Huy NT, Okamoto K, Chen H, Ayi I, Boakye DA, Bosompem KM, Hirayama K (2012) Immunoproteomics identification of major IgE and IgG4 reactive Schistosoma japonicum adult worm antigens using chronically infected human plasma. Trop Med Health 40(3):89–102.  https://doi.org/10.2149/tmh.2012-16 CrossRefPubMedPubMedCentralGoogle Scholar
  3. Burke ML, Jones MK, Gobert GN, Li YS, Ellis MK, McManus DP (2009) Immunopathogenesis of human schistosomiasis. Parasite Immunol 31(4):163–176.  https://doi.org/10.1111/j.1365-3024.2009.01098.x CrossRefPubMedGoogle Scholar
  4. Burke ML, McManus DP, Ramm GA, Duke M, Li Y, Jones MK, Gobert GN (2010) Temporal expression of chemokines dictates the hepatic inflammatory infiltrate in a murine model of schistosomiasis. PLoS Negl Trop Dis 4(2):e598.  https://doi.org/10.1371/journal.pntd.0000598 CrossRefPubMedPubMedCentralGoogle Scholar
  5. Cao S, Liu J, Song L, Ma X (2005) The protooncogene c-Maf is an essential transcription factor for IL-10 gene expression in macrophages. J Immunol 174:3484–3492CrossRefPubMedPubMedCentralGoogle Scholar
  6. Chuah C, Jones MK, McManus DP, Nawaratna SK, Burke ML, Owen HC, Ramm GA, Gobert GN (2016) Characterising granuloma regression and liver recovery in a murine model of Schistosomiasis japonica. Int J Parasitol 46(4):239–252.  https://doi.org/10.1016/j.ijpara.2015.12.004 CrossRefPubMedGoogle Scholar
  7. Colley DG, Bustinduy AL, Secor WE, King CH (2014) Human schistosomiasis. The Lancet 383(9936):2253–2264.  https://doi.org/10.1016/S0140-6736(13)61949-2
  8. Cope A, Le Friec G, Cardone J, Kemper C (2011) The Th1 life cycle: molecular control of IFN-gamma to IL-10 switching. Trends Immunol 32(6):278–286.  https://doi.org/10.1016/j.it.2011.03.010 CrossRefPubMedGoogle Scholar
  9. Coutinho HM, Acosta LP, Wu HW, McGarvey ST, Su L, Langdon GC, Jiz MA, Jarilla B, Olveda RM, Friedman JF, Kurtis JD (2007) Th2 cytokines are associated with persistent hepatic fibrosis in human Schistosoma japonicum infection. J Infect Dis 195(2):288–295.  https://doi.org/10.1086/510313 CrossRefPubMedGoogle Scholar
  10. Doenhoff MJ, Cioli D, Utzinger J (2008) Praziquantel: mechanisms of action, resistance and new derivatives for schistosomiasis. Curr Opin Infect Dis 21(6):659–667.  https://doi.org/10.1097/QCO.0b013e328318978f CrossRefPubMedGoogle Scholar
  11. Du X, Wu J, Zhang M, Gao Y, Zhang D, Hou M, Ji M, Wu G (2011) Upregulated expression of cytotoxicity-related genes in IFN-gamma knockout mice with Schistosoma japonicum infection. J Biomed Biotechnol 2011:864945.  https://doi.org/10.1155/2011/864945 1, 13CrossRefPubMedPubMedCentralGoogle Scholar
  12. Elbaz T, Esmat G (2013) Hepatic and intestinal schistosomiasis: review. J Adv Res 4(5):445–452.  https://doi.org/10.1016/j.jare.2012.12.001 CrossRefPubMedPubMedCentralGoogle Scholar
  13. Fan PC (2006) The history of schistosomiasis japonica in Taiwan. Kaohsiung J Med Sci 22(7):309–320.  https://doi.org/10.1016/s1607-551x(09)70317-1 CrossRefPubMedGoogle Scholar
  14. Finlay CM, Walsh KP, Mills KH (2014) Induction of regulatory cells by helminth parasites: exploitation for the treatment of inflammatory diseases. Immunol Rev 259(1):206–230.  https://doi.org/10.1111/imr.12164 CrossRefPubMedGoogle Scholar
  15. Hang L, Blum AM, Setiawan T, Urban JP Jr, Stoyanoff KM, Weinstock JV (2013) Heligmosomoides polygyrus bakeri infection activates colonic Foxp3+ T cells enhancing their capacity to prevent colitis. J Immunol 191(4):1927–1934.  https://doi.org/10.4049/jimmunol.1201457 CrossRefPubMedPubMedCentralGoogle Scholar
  16. He X, Sai X, Chen C, Zhang Y, Xu X, Zhang D, Pan W (2013) Host serum miR-223 is a potential new biomarker for Schistosoma japonicum infection and the response to chemotherapy. Parasit Vectors 6(1):272.  https://doi.org/10.1186/1756-3305-6-272 CrossRefPubMedPubMedCentralGoogle Scholar
  17. Ho IC, Lo D, Glimcher LH (1998) C-maf promotes T helper cell type 2 (Th2) and attenuates Th1 differentiation by both interleukin 4-dependent and -independent mechanisms. J Exp Med 188(10):1859–1866.  https://doi.org/10.1084/jem.188.10.1859 CrossRefPubMedPubMedCentralGoogle Scholar
  18. Hubner MP, Shi Y, Torrero MN, Mueller E, Larson D, Soloviova K, Gondorf F, Hoerauf A, Killoran KE, Stocker JT, Davies SJ, Tarbell KV, Mitre E (2012) Helminth protection against autoimmune diabetes in nonobese diabetic mice is independent of a type 2 immune shift and requires TGF-beta. J Immunol 188:559–568.  https://doi.org/10.4049/jimmunol.1100335 CrossRefPubMedGoogle Scholar
  19. Kanhere A, Hertweck A, Bhatia U, Gökmen MR, Perucha E, Jackson I, Lord GM, Jenner RG (2012) T-bet and GATA3 orchestrate Th1 and Th2 differentiation through lineage-specific targeting of distal regulatory elements. Nat Commun 3:1268.  https://doi.org/10.1038/ncomms2260 CrossRefPubMedPubMedCentralGoogle Scholar
  20. Katsurada F (1904) Schistosomum japonicum, ein Neuer Menschlicher Parasit. durch Welchen enine endemische Krankheit in Verschiedenen Gegenden Japans Veruracht wird. Annot Zool Jap 5:147–60Google Scholar
  21. Kim JI, Ho IC, Grusby MJ, Glimcher LH (1999) The transcription factor c-Maf controls the production of interleukin-4 but not other Th2 cytokines. Immunity 10(6):745–751.  https://doi.org/10.1016/S1074-7613(00)80073-4 CrossRefPubMedGoogle Scholar
  22. Kurata H, Lee HJ, O'Garra A, Arai N (1999) Ectopic expression of activated Stat6 induces the expression of Th2-specific cytokines and transcription factors in developing Th1 cells Immunity 11:677–688Google Scholar
  23. Layland LE, Mages J, Loddenkemper C, Hoerauf A, Wagner H, Lang R, da Costa CU (2010) Pronounced phenotype in activated regulatory T cells during a chronic helminth infection. J Immunol 184(2):713–724.  https://doi.org/10.4049/jimmunol.0901435 CrossRefPubMedGoogle Scholar
  24. Lighvani AA, Frucht DM, Jankovic D, Yamane H, Aliberti J, Hissong BD, Nguyen BV, Gadina M, Sher A, Paul WE, O'Shea JJ (2001) T-bet is rapidly induced by interferon-gamma in lymphoid and myeloid cells. Proc Natl Acad Sci U S A 98(26):15137–15142.  https://doi.org/10.1073/pnas.261570598 CrossRefPubMedPubMedCentralGoogle Scholar
  25. Liu J, Zhu C, Shi Y, Li H, Wang L, Qin S, Kang S, Huang Y, Jin Y, Lin J (2012) Surveillance of Schistosoma japonicum infection in domestic ruminants in the Dongting Lake region, Hunan province, China. PLoS One 7(2):e31876.  https://doi.org/10.1371/journal.pone.0031876 CrossRefPubMedPubMedCentralGoogle Scholar
  26. Liu YX, Wu W, Liang YJ, Jie ZL, Wang H, Wang W, Huang YX (2014) New uses for old drugs: the tale of artemisinin derivatives in the elimination of schistosomiasis japonica in China. Molecules (Basel, Switzerland) 19(9):15058–15074.  https://doi.org/10.3390/molecules190915058 CrossRefGoogle Scholar
  27. Maizels RM, Yazdanbakhsh M (2008) T-cell regulation in helminth parasite infections: implications for inflammatory diseases. Chem Immunol Allergy 94:112–123.  https://doi.org/10.1159/000154944 CrossRefPubMedGoogle Scholar
  28. McManus DP, Gray DJ, Li Y, Feng Z, Williams GM, Stewart D, Rey-Ladino J, Ross AG (2010) Schistosomiasis in the People’s Republic of China: the era of the Three Gorges Dam. Clin Microbiol Rev 23(2):442–466.  https://doi.org/10.1128/cmr.00044-09 CrossRefPubMedPubMedCentralGoogle Scholar
  29. Mishra PK, Palma M, Bleich D, Loke P, Gause WC (2014) Systemic impact of intestinal helminth infections. Mucosal Immunol 7(4):753–762.  https://doi.org/10.1038/mi.2014.23 CrossRefPubMedGoogle Scholar
  30. Morais CN et al (2008) Cytokine profile associated with chronic and acute human schistosomiasis mansoni. Mem Inst Oswaldo Cruz 103(6):561–568.  https://doi.org/10.1590/S0074-02762008000600009 CrossRefPubMedGoogle Scholar
  31. Reynolds LA, Maizels RM (2012) Cutting edge: in the absence of TGF-beta signaling in T cells, fewer CD103+ regulatory T cells develop, but exuberant IFN-gamma production renders mice more susceptible to helminth infection 189:(3)1113–1117  https://doi.org/10.4049/jimmunol.1200991
  32. Rutitzky LI, Smith PM, Stadecker MJ (2009) T-bet protects against exacerbation of schistosome egg-induced immunopathology by regulating Th17-mediated inflammation. Eur J Immunol 39(9):2470–2481.  https://doi.org/10.1002/eji.200939325 CrossRefPubMedPubMedCentralGoogle Scholar
  33. Sadler CH, Rutitzky LI, Stadecker MJ, Wilson RA (2003) IL-10 is crucial for the transition from acute to chronic disease state during infection of mice with Schistosoma mansoni. Eur J Immunol 33(4):880–888.  https://doi.org/10.1002/eji.200323501 CrossRefPubMedGoogle Scholar
  34. Salim A-M, Ismael AB (2014) Several immunological parameters in rabbit kittens born to S. japonicum-infected mothers. Open J Immunol 04(03):76–82.  https://doi.org/10.4236/oji.2014.43011 CrossRefGoogle Scholar
  35. Tamura T, Yanai H, Savitsky D, Taniguchi T (2008) The IRF family transcription factors in immunity and oncogenesis. Annu Rev Immunol 26(1):535–584.  https://doi.org/10.1146/annurev.immunol.26.021607.090400 CrossRefPubMedGoogle Scholar
  36. Tang J, Huang H, Ji X, Zhu X, Li Y, She M, Yan S, Fung M, Li Z (2014) Involvement of IL-13 and tissue transglutaminase in liver granuloma and fibrosis after Schistosoma japonicum infection. Mediat Inflamm 2014:753483.  https://doi.org/10.1155/2014/753483 1, 11Google Scholar
  37. Tang J, Zhu X, Zhao J, Fung M, Li Y, Gao Z, Yan S, Li X, Ji X, Su F, Li Z (2015) Tissue transglutaminase-regulated transformed growth factor-beta1 in the parasite links Schistosoma japonicum infection with liver fibrosis. Mediat Inflamm 2015:659378.  https://doi.org/10.1155/2015/659378 1, 11Google Scholar
  38. Taylor MD, van der Werf N, Maizels RM (2012) T cells in helminth infection: the regulators and the regulated. Trends Immunol 33(4):181–189.  https://doi.org/10.1016/j.it.2012.01.001 CrossRefPubMedGoogle Scholar
  39. Turner JD, Jenkins GR, Hogg KG, Aynsley SA, Paveley RA, Cook PC, Coles MC, Mountford AP (2011) CD4+CD25+ regulatory cells contribute to the regulation of colonic Th2 granulomatous pathology caused by schistosome infection. PLoS Negl Trop Dis 5(8):e1269.  https://doi.org/10.1371/journal.pntd.0001269 CrossRefPubMedPubMedCentralGoogle Scholar
  40. Usui T, Preiss JC, Kanno Y, Yao ZJ, Bream JH, O'Shea JJ, Strober W (2006) T-bet regulates Th1 responses through essential effects on GATA-3 function rather than on IFNG gene acetylation and transcription. J Exp Med 203(3):755–766.  https://doi.org/10.1084/jem.20052165 CrossRefPubMedPubMedCentralGoogle Scholar
  41. Wang W, Dai JR, Liang YS (2014) Apropos: factors impacting on progress towards elimination of transmission of schistosomiasis japonica in China. Parasit Vectors 7(1):408.  https://doi.org/10.1186/1756-3305-7-408 CrossRefPubMedPubMedCentralGoogle Scholar
  42. Wilson MS, Mentink-Kane MM, Pesce JT, Ramalingam TR, Thompson R, Wynn TA (2007) Immunopathology of schistosomiasis. Immunol Cell Biol 85(2):148–154.  https://doi.org/10.1038/sj.icb.7100014 CrossRefPubMedGoogle Scholar
  43. Wohlfert EA, Grainger JR, Bouladoux N, Konkel JE, Oldenhove G, Ribeiro CH, Hall JA, Yagi R, Naik S, Bhairavabhotla R, Paul WE, Bosselut R, Wei G, Zhao K, Oukka M, Zhu J, Belkaid Y (2011) GATA3 controls Foxp3(+) regulatory T cell fate during inflammation in mice. J Clin Invest 121(11):4503–4515.  https://doi.org/10.1172/jci57456 CrossRefPubMedPubMedCentralGoogle Scholar
  44. Wu ZD, Lv ZY, Yu XB (2005) Development of a vaccine against Schistosoma japonicum in China: A review. Acta Tropica. 96:106–116.  https://doi.org/10.1016/j.actatropica.2005.08.005
  45. Xu J et al (2009) c-Maf regulates IL-10 expression during Th17 polarization. J Immunol 182:6226–6236.  https://doi.org/10.4049/jimmunol.0900123 CrossRefPubMedPubMedCentralGoogle Scholar
  46. Xu X, Wen X, Chi Y, He L, Zhou S, Wang X, Zhao J, Liu F, Su C (2010) Activation-induced T helper cell death contributes to Th1/Th2 polarization following murine Schistosoma japonicum infection. J Biomed Biotechnol 2010:202397.  https://doi.org/10.1155/2010/202397 1, 12PubMedPubMedCentralGoogle Scholar
  47. Yu L, Sun X, Yang F, Yang J, Shen J, Wu Z (2012) Inflammatory cytokines IFN-gamma, IL-4, IL-13 and TNF-alpha alterations in schistosomiasis: a meta-analysis. Parasitol Res 110(4):1547–1552.  https://doi.org/10.1007/s00436-011-2661-4 CrossRefPubMedGoogle Scholar
  48. Zhou YB, Liang S, Jiang QW (2012) Factors impacting on progress towards elimination of transmission of schistosomiasis japonica in China. Parasit Vectors 5(1):275.  https://doi.org/10.1186/1756-3305-5-275 CrossRefPubMedPubMedCentralGoogle Scholar
  49. Zhou S, Jin X, Chen X, Zhu J, Xu Z, Wang X, Liu F, Hu W, Zhou L, Su C (2015) Heat shock protein 60 in eggs specifically induces Tregs and reduces liver immunopathology in mice with Schistosomiasis japonica. PLoS One 10(9):e0139133.  https://doi.org/10.1371/journal.pone.0139133 CrossRefPubMedPubMedCentralGoogle Scholar
  50. Zhu J (2010) Transcriptional regulation of Th2 cell differentiation. Immunol Cell Biol 88(3):244–249.  https://doi.org/10.1038/icb.2009.114 CrossRefPubMedPubMedCentralGoogle Scholar
  51. Zhu J, Min B, Hu-Li J, Watson CJ, Grinberg A, Wang Q, Killeen N, Urban JF, Guo L, Paul WE (2004) Conditional deletion of Gata3 shows its essential function in T(H)1-T(H)2 responses. Nat Immunol 5(11):1157–1165.  https://doi.org/10.1038/ni1128 CrossRefPubMedGoogle Scholar
  52. Zhu J, Guo L, Watson CJ, Hu-Li J, Paul WE (2001) Stat6 is necessary and sufficient for IL-4’s role in Th2 differentiation and cell expansion. J Immunol 166:7276–7281CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2017

Authors and Affiliations

  1. 1.Department of Clinical Laboratory and Hematology, School of MedicineJiangsu UniversityZhenjiangPeople’s Republic of China
  2. 2.Department of Parasitology & Medical Entomology, Faculty of Medical Laboratory SciencesUniversity of KhartoumKhartoumSudan

Personalised recommendations