Activation of transforming growth factor beta by malaria parasite-derived metalloproteinases and a thrombospondin-like molecule.
Much of the pathology of malaria is mediated by inflammatory cytokines (such as interleukin 12, interferon gamma, and tumor necrosis factor alpha), which are part of the immune response that kills the parasite. The antiinflammatory cytokine transforming growth factor (TGF)-beta plays a crucial role in preventing the severe pathology of malaria in mice and TGF-beta 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-beta (LatTGF-beta) 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-beta binding motifs of TSP, all inhibit malaria-mediated TGF-beta activation. Importantly, TRAP-deficient P. berghei parasites are less able to activate LatTGF-beta than wild-type parasites and their replication is attenuated in vitro. We show that activation of TGF-beta by malaria parasites is a two step process involving TSP-like molecules and metalloproteinase activity. Activation of LatTGF-beta represents a novel mechanism for direct modulation of the host response by malaria parasites.
Omer
Fakhreldin M
FM
Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT, United Kingdom.
de Souza
J Brian
JB
Corran
Patrick H
PH
Sultan
Ali A
AA
Riley
Eleanor M
EM
D000595:Amino Acid Sequence; D000818:Animals; D004912:Erythrocytes / Q000469:parasitology; D045726:Metalloproteases / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D010961:Plasmodium / Q000201:enzymology / Q000502:physiology*; D015800:Protozoan Proteins / Q000502:physiology*; D019700:Thrombospondin 1 / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000378:metabolism*
D015800:Protozoan Proteins; D019700:Thrombospondin 1; D016212:Transforming Growth Factor beta; D045726:Metalloproteases