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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

Abstract

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.

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Acknowledgements

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). https://doi.org/10.1038/35003208

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