Skip to main content
Log in

Antimicrobial effects of murine mesenchymal stromal cells directed against Toxoplasma gondii and Neospora caninum: role of immunity-related GTPases (IRGs) and guanylate-binding proteins (GBPs)

  • Original Investigation
  • Published:
Medical Microbiology and Immunology Aims and scope Submit manuscript

Abstract

Mesenchymal stromal cells (MSCs) have a multilineage differentiation potential and provide immunosuppressive and antimicrobial functions. Murine as well as human MSCs restrict the proliferation of T cells. However, species-specific differences in the underlying molecular mechanisms have been described. Here, we analyzed the antiparasitic effector mechanisms active in murine MSCs. Murine MSCs, in contrast to human MSCs, could not restrict the growth of a highly virulent strain of Toxoplasma gondii (BK) after stimulation with IFN-γ. However, the growth of a type II strain of T. gondii (ME49) was strongly inhibited by IFN-γ-activated murine MSCs. Immunity-related GTPases (IRGs) as well as guanylate-binding proteins (GBPs) contributed to this antiparasitic effect. Further analysis showed that IFN-γ-activated mMSCs also inhibit the growth of Neospora caninum, a parasite belonging to the apicomplexan group as well. Detailed studies with murine IFN-γ-activated MSC indicated an involvement in IRGs like Irga6, Irgb6 and Irgd in the inhibition of N. caninum. Additional data showed that, furthermore, GBPs like mGBP1 and mGBP2 could have played a role in the anti-N. caninum effect of murine MSCs. These data underline that MSCs, in addition to their regenerative and immunosuppressive activity, function as antiparasitic effector cells as well. However, IRGs are not present in the human genome, indicating a species-specific difference in anti-T. gondii and anti-N. caninum effect between human and murine MSCs.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Caplan A (2007) Adult mesenchymal stem cells for tissue engineering versus regenerative medicine. J Cell Physiol 213:341–347

    Article  PubMed  CAS  Google Scholar 

  2. Shi M, Liu ZW, Wang FS (2011) Immunomodulatory properties and therapeutic application of mesenchymal stem cells. Clin Exp Immunol 164:1–8

    Article  PubMed  CAS  Google Scholar 

  3. Meisel R, Zibert A, Laryea M, Göbel U, Däubener W, Dilloo D (2004) Human bone marrow stromal cells inhibit allogeneic T-cell responses by indoleamine 2,3-dioxygenase-mediated tryptophan degradation. Blood 103:4619–4621

    Article  PubMed  CAS  Google Scholar 

  4. Shi Y, Hu G, Su J, Li W, Chen Q, Shou P, Xu C, Chen X, Huang Y, Zhu Z, Huang X, Han S, Xie N, Ren G (2010) Mesenchymal stem cells: a new strategy for immunosuppression and tissue repair. Cell Res 20:510–518

    Article  PubMed  CAS  Google Scholar 

  5. Sattler C, Steinsdoerfer M, Offers M, Fischer E, Schierl R, Heseler K, Däubener W, Seissler J (2011) Inhibition of T-cell proliferation by murine multipotent mesenchymal stromal cells is mediated by CD39 expression and adenosine generation. Cell Transplant 20:1221–1230

    Article  PubMed  Google Scholar 

  6. Lanz TV, Opitz CA, Ho PP, Agrawal A, Lutz C, Weller M, Mellor AL, Steinman L, Wick W, Platten M (2010) Mouse mesenchymal stem cells suppress antigen-specific TH cell immunity independent of indoleamine 2,3-dioxygenase 1 (IDO1). Stem Cells Dev 19:657–668

    Article  PubMed  CAS  Google Scholar 

  7. Maggini J, Mirkin G, Bognanni I, Holmberg J, Piazzon IM, Nepomnaschy I, Costa H, Canones C, Raiden S, Vermeulen M, Geffner JR (2010) Mouse bone marrow-derived mesenchymal stromal cells turn activated macrophages into a regulatory-like profile. PLoS One 5:e9252

    Article  PubMed  Google Scholar 

  8. Spaggiari GM, Abdelrazik H, Becchetti F, Moretta L (2009) MSCs inhibit monocyte-derived DC maturation and function by selectively interfering with the generation of immature DCs: central role of MSC-derived prostaglandin E2. Blood 113:6576–6583

    Article  PubMed  CAS  Google Scholar 

  9. Meisel R, Brockers S, Heseler K, Degistirici Ö, Bülle H, Woite C, Stuhlsatz S, Schwippert W, Jäger M, Sorg RV, Henschler R, Seissler J, Dilloo D, Däubener W (2011) Human but not murine multipotent mesenchymal stromal cells exhibit broad-spectrum antimicrobial effector function mediated by indoleamine 2,3-dioxygenase. Leukemia 25:648–654

    Article  PubMed  CAS  Google Scholar 

  10. Howe DK, Sibley LD (1995) Toxoplasma gondii comprises three clonal lineages: correlation of parasite genotype with human disease. J Infect Dis 172:1561–1566

    Article  PubMed  CAS  Google Scholar 

  11. Lin Y, Hogan WJ (2011) Clinical application of mesenchymal stem cells in the treatment and prevention of graft-versus-host disease. Adv Hematol 2011:427863

    PubMed  Google Scholar 

  12. Montoya JG, Liesenfeld O (2004) Toxoplasmosis. Lancet 363:1965–1976

    Article  PubMed  CAS  Google Scholar 

  13. Zhao Y, Ferguson DJ, Wilson DC, Howard JC, Sibley LD, Yap GS (2009) Virulent Toxoplasma gondii evade immunity-related GTPase-mediated parasite vacuole disruption within primed macrophages. J Immunol 182:3775–3781

    Article  PubMed  CAS  Google Scholar 

  14. Liesenfeld O, Parvanova I, Zerrahn J, Han SJ, Heinrich F, Munoz M, Kaiser F, Aebischer T, Buch T, Waisman A, Reichmann G, Utermöhlen O, von Stebut E, von Loewenich FD, Bogdan C, Specht S, Saeftel M, Hoerauf A, Mota MM, Krönen-Waisman S, Kaufmann SH, Howard JC (2011) The IFN-γ-inducible GTPase, Irga6, protects mice against Toxoplasma gondii but not against Plasmodium berghei and some other intracellular pathogens. PLoS One 6:e20568

    Article  PubMed  CAS  Google Scholar 

  15. Dubey JP, Schares G, Ortega-Mora LM (2007) Epidemiology and control of neosporosis and Neospora caninum. Clin Microbiol Rev 20:323–367

    Article  PubMed  CAS  Google Scholar 

  16. Pereira Garcia-Melo D, Regidor-Cerrillo J, Collantes-Fernandez E, Aguado-Martinez A, Del Pozo I, Minguijon E, Gomez-Bautista M, Aduriz G, Ortega-Mora LM (2010) Pathogenic characterization in mice of Neospora caninum isolates obtained from asymptomatic calves. Parasitology 137:1057–1068

    Article  PubMed  CAS  Google Scholar 

  17. Regidor-Cerrillo J, Gomez-Bautista M, Sodupe I, Aduriz G, Alvarez-Garcia G, Del Pozo I, Ortega-Mora LM (2011) In vitro invasion rate comprise virulence-related phenotypic traits of Neospora caninum. Vet Res 42:41

    Article  PubMed  Google Scholar 

  18. Degrandi D, Konermann C, Beuter-Gunia C, Kresse A, Würthner J, Kurig S, Beer S, Pfeffer K (2007) Extensive characterization of IFN-induced GTPases mGBP1 to MGBP10 involved in host defense. J Immunol 179:7729–7740

    PubMed  CAS  Google Scholar 

  19. Sonda S, Fuchs N, Connolly B, Fernandez P, Gottstein B, Hemphill A (1998) The major 36 kDa Neospora caninum tachyzoites surface protein is closely related to the major Toxoplasma gondii surface antigen. Mol Biochem Parasit 97:97–108

    Article  CAS  Google Scholar 

  20. Spekker K, Czesla M, Ince V, Heseler K, Schmidt SK, Schares G, Däubener W (2009) Indoleamine 2,3-dioxygenase is involved in defense against Neospora caninum in human and bovine cells. Infect Immun 77:4496–4501

    Article  PubMed  CAS  Google Scholar 

  21. Adams LB, Hibbs JB, Taintor RR, Krahenbuhl JL (1990) Microbiostatic effect of murine-activated macrophages for Toxoplasma gondii. Role for synthesis of inorganic nitrogen oxides from l-arginine. J Immunol 144:2725–2729

    PubMed  CAS  Google Scholar 

  22. Scharton-Kersten TM, Yap G, Magram J, Sher A (1997) Inducible nitric oxide is essential for host control of persistent but not acute infection with the intracellular pathogen Toxoplasma gondii. J Exp Med 185:1261–1273

    Article  PubMed  CAS  Google Scholar 

  23. Könen-Waisman S, Howard JC (2007) Cell-autonomous immunity to Toxoplasma gondii in mouse and man. Microbes Infect 9:1652–1661

    Article  PubMed  Google Scholar 

  24. Taylor GA, Collazo CM, Yap GS, Nguyen K, Gregorio TA, Taylor LS, Eagleson B, Secrest L, Southon EA, Reid SW, Tessarollo L, Bray M, McVicar DW, Komschlies KL, Young HA, Biron CA, Sher A, Woude GF (2000) Pathogen-specific loss of host resistance in mice lacking the IFN-gamma-inducible gene IGTP. Proc Natl Acad Sci USA 97:751–757

    Article  PubMed  CAS  Google Scholar 

  25. Taylor GA, Feng CG, Sher A (2004) p47 GTPases: regulators of immunity to intracellular pathogens. Nat Rev Immunol 4:100–119

    Article  PubMed  CAS  Google Scholar 

  26. Howard JC, Hunn JP, Steinfeldt T (2011) The IRG protein-based resistance mechanism in mice and its relation to virulence in Toxoplasma gondii. Curr Opin Microbiol 14:414–421

    Article  PubMed  CAS  Google Scholar 

  27. Martens S, Parvanova I, Zerrahn J, Griffiths G, Schell G, Reichmann G, Howard JC (2005) Disruption of Toxoplasma gondii parasitophorous vacuoles by the mouse p57-resistance GTPases. PLoS Pathogen 3:e24

    Article  Google Scholar 

  28. Steinfeld T, Könen-Waismann S, Tong L, Pawlowski N, Lamkemeyer T, Sibley LD, Hunn JP, Howard JC (2010) Phosphorylation of mouse immunity-related GTPase (IRG) resistance proteins is an evasion strategy for virulent Toxoplasma gondii. PLoS Biol 8:e1000576

    Article  Google Scholar 

  29. Reid AJ, Vermont SJ, Cotton JA, Harris D, Hill-Cawthorne GA, Könen-Waisman S, Latham SM, Mourier T, Norton R, Quail MA, Sanders M, Shanmugam D, Sohal A, Wasmuth JD, Brunk B, Grigg ME, Howard JC, Parkinson J, Roos DS, Trees AJ, Berriman M, Pain A, Wastling JM (2012) Comparative genomics of the apicomplexan parasites Toxoplasma gondii and Neospora caninum. Coccidia differing in host range and transmission strategy. PLoS Pathogen 8:e1002567

    Article  CAS  Google Scholar 

  30. Yamamoto M, Ma JS, Mueller C, Kamiyama N, Saiga H, Kubo E, Kimura T, Okamoto T, Okuyama M, Kayama H, Nagamune K, Takashima S, Matsuura Y, Soldati-Favre D, Takeda K (2011) ATF6beta is a host cellular target of the Toxoplasma gondii virulence factor ROP18. J Exp Med 208:1533–1546

    Article  PubMed  CAS  Google Scholar 

  31. Niedelman W, Gold DA, Rosowski EE, Sprokholt JK, Lim D, Farid Arenas A, Melo MB, Spooner E, Yaffe MB, Saeij JP (2012) The rhoptry proteins ROP18 and ROP5 mediate toxoplasma gondii evasion of the murine, but not the human, interferon-gamma response. PLoS Pathog 8:e1002784

    Article  PubMed  CAS  Google Scholar 

  32. Bekpen C, Hunn JP, Rhode C, Parvanova I, Guethlein L, Dunn DM, Glowalla E, Leptin M, Howard JC (2005) The interferon-inducible p47 (IRG) GTPases in vertebrates: loss of the cell autonomous resistance mechanism in the human lineage. Genom Biol 6:r92

    Article  Google Scholar 

  33. Gorbacheva VY, Lindner D, Sen GV, Vestal DJ (2001) The interferon (IFN)-induced GTPase. mGBP2. Role in IFN-gamma-induced murine fibroblast proliferation. J Biol Chem 277:6080–6087

    Article  PubMed  Google Scholar 

  34. Guenzi E, Töpolt K, Lubeseder-Martellato C, Jörg A, Naschberger E, Benelli R, Albini A, Stürzel M (2003) The guanylate binding protein-1 GTPase controls the invasive and angiogenic capability of endothelial cells through inhibition of MMP-1 expression. EMBO J 22:3772–3782

    Article  PubMed  CAS  Google Scholar 

  35. Anderson SL, Cartpon JM, Lou J, Rubin BY (1999) Interferon-induced guanylate binding protein-1 (GBP-1) mediates an antiviral effect against vesicular stomatitis virus and encephalomyocarditis virus. Virology 256:8–14

    Article  PubMed  CAS  Google Scholar 

  36. Kim BH, Shenoy AR, Kumar P, Das R, Tiwari S, MacMicking JD (2011) A family of IFN-gamma-inducible 65-kD GTPases protects against bacterial infection. Science 332:717–721

    Article  PubMed  CAS  Google Scholar 

  37. Yamamoto M, Okuyama M, Ma JS, Kimura T, Kamiyama N, Saiga H, Ohshima J, Sasai M, Kayama H, Okamoto T, Huang DC, Soldati-Favre D, Horie K, Takeda J, Takeda K (2012) A cluster of interferon-g-inducible p65 GTPases plays a critical role in host defense against Toxoplasma gondii. Immunity 37:302–313

    Google Scholar 

  38. Virreira-Winter S, Niedelman W, Jensen KD, Rosowski EE, Julien L, Spooner E, Cardonna K, Burleigh BA, Saeij JPJ, Ploegh HL, Frickel EM (2011) Determinants of GBP recruitment to Toxoplasma gondii vacuoles and the parasitic factor that control it. PLoS One 6:e24434

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

This study was supported by German Federal Ministry of Education and Research (BMBF) program “MSC pro Isle” (to W. D., R. M., J. S., R. V. S.), “ToxoNet02” (to W. D., G. S.), German Research Concil (DFG) (to WD, K. P. P.), Manchot-Graduate School (to W. D., K. P.) and the “Elterninitiative Kinderkrebsklinik Düsseldorf e.V.” (R. M.).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to W. Däubener.

Additional information

K. Spekker and M. Leineweber contributed equally to this work.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Spekker, K., Leineweber, M., Degrandi, D. et al. Antimicrobial effects of murine mesenchymal stromal cells directed against Toxoplasma gondii and Neospora caninum: role of immunity-related GTPases (IRGs) and guanylate-binding proteins (GBPs). Med Microbiol Immunol 202, 197–206 (2013). https://doi.org/10.1007/s00430-012-0281-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00430-012-0281-y

Keywords

Navigation