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Uptake of apoptotic cells drives the growth of a pathogenic trypanosome in macrophages

An Erratum to this article was published on 20 April 2000


After apoptosis, phagocytes prevent inflammation and tissue damage by the uptake and removal of dead cells1. In addition, apoptotic cells evoke an anti-inflammatory response through macrophages2,3. We have previously shown that there is intense lymphocyte apoptosis in an experimental model of Chagas' disease4, a debilitating cardiac illness caused by the protozoan Trypanosoma cruzi. Here we show that the interaction of apoptotic, but not necrotic T lymphocytes with macrophages infected with T. cruzi fuels parasite growth in a manner dependent on prostaglandins, transforming growth factor-β (TGF-β) and polyamine biosynthesis. We show that the vitronectin receptor is critical, in both apoptotic-cell cytoadherence and the induction of prostaglandin E2/TGF-β release and ornithine decarboxylase activity in macrophages. A single injection of apoptotic cells in infected mice increases parasitaemia, whereas treatment with cyclooxygenase inhibitors almost completely ablates it in vivo. These results suggest that continual lymphocyte apoptosis and phagocytosis of apoptotic cells by macrophages have a role in parasite persistence in the host, and that cyclooxygenase inhibitors have potential therapeutic application in the control of parasite replication and spread in Chagas' disease.

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Figure 1: Apoptotic cells exacerbate parasite growth in T. cruzi infection.
Figure 2: Effects of apoptotic cells on macrophages infected with T. cruzi are mediated by the vitronectin receptor. αv (a) and β3 (b) VnR chains are expressed by macrophages from infected (lower panels), but not uninfected (upper panels), mice.
Figure 3: Effects of apoptotic cells on macrophages infected with T. cruzi depend on TGF-β.
Figure 4: In vitro and in vivo effects of COX inhibitors on T. cruzi infection.


  1. 1

    Savill, J. Apoptosis: Phagocytic docking without shocking. Nature 392, 442–443 (1998).

    CAS  Article  ADS  Google Scholar 

  2. 2

    Voll, R. E., Herrmann, M., Roth, E. A., Stach, C. & Kalden, J. R. Immunosuppressive effects of apoptotic cells. Nature 390, 350–351 (1997).

    CAS  Article  ADS  Google Scholar 

  3. 3

    Fadok, V. A. et al. Macrophages that have ingested apoptotic cells in vitro inhibit proinflammatory cytokine production through autocrine/paracrine mechanisms involving TGF-β, PGE2 and PAF. J. Clin. Invest. 101, 890–898 (1998).

    CAS  Article  Google Scholar 

  4. 4

    Lopes, M. F., Veiga, V. F., Santos, A. R., Fonseca, M. E. F. & DosReis, G. A. Activation-induced CD4+ T cell death by apoptosis in experimental Chagas disease. J. Immunol. 154, 744–752 (1995).

    CAS  PubMed  Google Scholar 

  5. 5

    Nunes, M. P., Andrade, R. M., Lopes, M. F. & DosReis, G. A. Activation-induced T cell death exacerbates Trypanosoma cruzi replication in macrophages cocultured with CD4+ T lymphocytes from infected hosts. J. Immunol. 160, 1313–1319 (1998).

    CAS  PubMed  Google Scholar 

  6. 6

    Savill, J., Dransfield, I., Hogg, N. & Haslett, C. Vitronectin receptor-mediated phagocytosis of cells undergoing apoptosis. Nature 343, 170–173 (1990).

    CAS  ADS  Google Scholar 

  7. 7

    Savill, J., Hogg, N., Ren, Y. & Haslett, C. Thrombospondin cooperates with CD36 and the vitronectin receptor in macrophage recognition of neutrophils undergoing apoptosis. J. Clin. Invest. 90, 1513–1522 (1992).

    CAS  Article  Google Scholar 

  8. 8

    Silva, J. S., Twardzik, D. R. & Reed, S. G. Regulation of Trypanosoma cruzi infection in vitro and in vivo by transforming growth factor β (TGF-β). J. Exp. Med. 174, 539–545 (1991).

    CAS  Article  Google Scholar 

  9. 9

    Ming, M., Ewen, M. E. & Pereira, M. E. A. Trypanosome invasion of mammalian cells requires activation of the TGF-β signaling pathway. Cell 82, 287–296 (1995).

    CAS  Article  Google Scholar 

  10. 10

    Gazzinelli, R. T., Oswald, I. P., Hieny, S., James, S. L. & Sher, A. The microbicidal activity of interferon-γ-treated macrophages against Trypanosoma cruzi involves an L-arginine-dependent, nitrogen oxide-mediated mechanism inhibitable by interleukin-10 and transforming growth factor-β. Eur. J. Immunol. 22, 2501–2506 (1992).

    CAS  Article  Google Scholar 

  11. 11

    Boutard, V. et al. Transforming growth factor-β stimulates arginase activity in macrophages: implications for the regulation of macrophage cytoxocity. J. Immunol. 155, 2077–2084 (1995).

    CAS  PubMed  Google Scholar 

  12. 12

    Pegg, A. E. & McCann, P. P. Polyamine metabolism and function. Am. J. Physiol. 243, C212–221 (1982).

    CAS  Article  Google Scholar 

  13. 13

    Kierszembaum, F., Wirth, J. J., McCann, P. P. & Sjoerdsma, A. Arginine decarboxylase inhibitors reduce the capacity of Trypanosoma cruzi to infect and multiply in mammalian host cells. Proc. Natl Acad. Sci. USA 84, 4278–4282 (1987).

    Article  ADS  Google Scholar 

  14. 14

    Hunter, K. J., Le Quesne, S. A. & Fairlamb, A. H. Identification and biosynthesis of N1,N9-bis(glutathionyl)aminopropylcadaverine (homotrypanothione) in Trypanosoma cruzi. Eur. J. Biochem. 226, 1019–1027 (1994).

    CAS  Article  Google Scholar 

  15. 15

    Mamont, P. S. et al. α-Methyl ornithine, a potent competitive inhibitor of ornithine decarboxylase, blocks proliferation of rat hepatoma cells in culture. Proc. Natl Acad. Sci. USA 73, 1626–1630 (1976).

    CAS  Article  ADS  Google Scholar 

  16. 16

    Corraliza, I. M., Modolell, M., Ferber, E. & Soler, G. Involvement of protein kinase A in the induction of arginase in murine bone marrow-derived macrophages. Biochim. Biophys. Acta 1334, 123–128 (1997).

    CAS  Article  Google Scholar 

  17. 17

    Prosser, F. H. & Wahl, L. M. Involvement of the ornithine decarboxylase pathway in macrophage collagenase production. Arch. Biochem. Biophys. 260, 218–225 (1998).

    Article  Google Scholar 

  18. 18

    Meade, E. A., Smith, W. L. & DeWitt, D. L. Differential inhibition of prostaglandin endoperoxide synthase (cyclooxygenase) isozymes by aspirin and other non-steroidal anti-inflammatory drugs. J. Biol. Chem. 268, 6610–6614 (1993).

    CAS  PubMed  Google Scholar 

  19. 19

    Futaki, N. et al. Selective inhibition of NS-398 on prostanoid production in inflamed tissue in rat carrageenan-air-pouch inflammation. J. Pharm. Pharmacol. 45, 753–755 (1993).

    CAS  Article  Google Scholar 

  20. 20

    Jiang, C., Ting, A. T. & Seed, B. PPAR-γ agonists inhibit production of monocyte inflammatory cytokines. Nature 391, 82–85 (1998).

    CAS  Article  ADS  Google Scholar 

  21. 21

    Celentano, A. M. et al. PGE2 involvement in experimental infection with Trypanosoma cruzi subpopulations. Prostaglandins 49, 141–153 (1995).

    CAS  Article  Google Scholar 

  22. 22

    Contreras, V. T., Salles, J. M., Thomas, N., Morel, C. M. & Goldenberg, S. In vitro differentiation of Trypanosoma cruzi under chemically defined conditions. Mol. Biochem. Parasitol. 16, 315–327 (1985).

    CAS  Article  Google Scholar 

  23. 23

    Griffith, T. S., Yu, X., Herndon, J. M., Green, D. R. & Ferguson, T. A. CD95-induced apoptosis of lymphocytes in an immune privileged site induces immunological tolerance. Immunity 5, 7–16 (1996).

    CAS  Article  Google Scholar 

  24. 24

    Sturmer, A. M., Driscoll, D. P. & Jackson-Matthews, D. E. A quantitative immunoassay using chicken antibodies for detection of native and recombinant α-amidating enzyme. J. Immunol. Methods 146, 105–110 (1992).

    CAS  Article  Google Scholar 

  25. 25

    Maxfield, S. R. et al. Murine T cells express a cell surface receptor for multiple extracellular matrix proteins. Identification and characterization with monoclonal antibodies. J. Exp. Med. 169, 2173–2190 (1989).

    CAS  Article  Google Scholar 

  26. 26

    Yokoyama, W. M. et al. Characterization of a cell surface-expressed disulfide-linked dimer involved in murine T cell activation. J. Immunol. 141, 369–376 (1988).

    CAS  PubMed  Google Scholar 

  27. 27

    Soares, M. B. P., David, J. R. & Titus, R. G. An in vitro model for infection with Leishmania major that mimics the immune response in mice. Infect. Immun. 65, 2837–2845 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. 28

    Green, L. C. et al. Analysis of nitrate, nitrite and [15N] nitrate in biological fluids. Anal. Biochem. 126, 131–138 (1982).

    CAS  Article  Google Scholar 

  29. 29

    De Mello, F. G., Bachrach, U. & Nirenberg, M. Ornithine and glutamic acid decarboxylase activities in the developing chick retina. J. Neurochem. 27, 847–851 (1976).

    CAS  Article  Google Scholar 

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We thank E. M. Shevach, M. Lenardo and V. Laurentino for the gifts of peptides and antibodies; and M. A. Vannier dos Santos for reading the manuscript and for helpful discussions. This work was supported by CNPq, FAPERJ, FUJB-UFRJ and PRONEX. C.F.L. is a doctoral fellow of Institute of Microbiology (UFRJ).

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Correspondence to George A. DosReis or Marcela F. Lopes.

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Freire-de-Lima, C., Nascimento, D., Soares, M. et al. Uptake of apoptotic cells drives the growth of a pathogenic trypanosome in macrophages. Nature 403, 199–203 (2000).

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