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Activation of Transforming Growth Factor ß by Malaria Parasite-derived Metalloproteinases and a Thrombospondin-like Molecule
2 Department of Immunology and Molecular Pathology, Royal Free and University College London Medical School, London W1T 4JF, United Kingdom
3 Division of Immunobiology, National Institute for Biological Standards and Control, Herts EN6 3QG, United Kingdom
4 Department of Pathology, Michael Heidelberger Division of Immunology, New York University School of Medicine, New York, NY 10016
Address correspondence to Eleanor M. Riley, Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT, United Kingdom. Phone: 44-207-927-2706; Fax: 44-207-927-2807; email: eleanor.riley{at}lshtm.ac.uk
Much of the pathology of malaria is mediated by inflammatory cytokines (such as interleukin 12, interferon
, and tumor necrosis factor 
), which are part of the immune response that kills the parasite. The antiinflammatory cytokine transforming growth factor (TGF)-ß plays a crucial role in preventing the severe pathology of malaria in mice and TGF-ß production is associated with reduced risk of clinical malaria in humans. Here we show that serum-free preparations of Plasmodium falciparum, Plasmodium yoelii 17XL, and Plasmodium berghei schizont-infected erythrocytes, but not equivalent preparations of uninfected erythrocytes, are directly able to activate latent TGF-ß (LatTGF-ß) in vitro. Antibodies to thrombospondin (TSP) and to a P. falciparum TSP-related adhesive protein (PfTRAP), and synthetic peptides from PfTRAP and P. berghei TRAP that represent homologues of TGF-ß binding motifs of TSP, all inhibit malaria-mediated TGF-ß activation. Importantly, TRAP-deficient P. berghei parasites are less able to activate LatTGF-ß than wild-type parasites and their replication is attenuated in vitro. We show that activation of TGF-ß by malaria parasites is a two step process involving TSP-like molecules and metalloproteinase activity. Activation of LatTGF-ß represents a novel mechanism for direct modulation of the host response by malaria parasites.
Key Words: parasitic protozoa • malaria, falciparum • transforming growth factor ß • matrix metalloproteinases • thrombospondin 1
Abbreviations used in this paper: huLatTGF-ß, latent human TGF-ß; LAP, latency-associated protein; LatTGF-ß, latent TGF-ß; MMP, metalloproteinase; PbTRAP, P. berghei thrombospondin-related adhesive protein; Pb TRAP ko, PbTRAP knockout; Pb WT, wild-type P. berghei; PfSL, P. falciparum schizont lysate; PfTRAP, P. falciparum thrombospondin-related adhesive protein; pRBC, parasitized RBC; rHuTSP-1, recombinant human thrombospondin 1; rLatTGF-ß, recombinant latent human TGF-ß; TSP, thrombospondin; uRBC, uninfected RBC.
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