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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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