Activation of Transforming Growth Factor β by Malaria Parasite-derived Metalloproteinases and a Thrombospondin-like Molecule

Fakhreldin M. Omer, J. Brian De Souza, Patrick H. Corran, Ali Sultan, Eleanor M. Riley

Research output: Contribution to journalArticle

48 Citations (Scopus)

Abstract

Much of the pathology of malaria is mediated by inflammatory cytokines (such as interleukin 12, interferon γ, and tumor necrosis factor α), which are part of the immune response that kills the parasite. The antiinflammatory cytokine transforming growth factor (TGF)-β plays a crucial role in preventing the severe pathology of malaria in mice and TGF-β 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-β (LatTGF-β) 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-β binding motifs of TSP, all inhibit malaria-mediated TGF-β activation. Importantly, TRAP-deficient P. berghei parasites are less able to activate LatTGF-β than wild-type parasites and their replication is attenuated in vitro. We show that activation of TGF-β by malaria parasites is a two step process involving TSP-like molecules and metalloproteinase activity. Activation of LatTGF-β represents a novel mechanism for direct modulation of the host response by malaria parasites.

Original languageEnglish
Pages (from-to)1817-1827
Number of pages11
JournalJournal of Experimental Medicine
Volume198
Issue number12
DOIs
Publication statusPublished - 15 Dec 2003
Externally publishedYes

Fingerprint

Thrombospondins
Transforming Growth Factors
Metalloproteases
Malaria
Parasites
Plasmodium berghei
Plasmodium falciparum
Adhesives
Erythrocytes
Plasmodium yoelii
Pathology
Cytokines
Schizonts
Interleukin-12
Interferons
Proteins
Anti-Inflammatory Agents
Tumor Necrosis Factor-alpha
Antibodies
Serum

Keywords

  • Malaria, falciparum
  • Matrix metalloproteinases
  • Parasitic protozoa
  • Thrombospondin 1
  • Transforming growth factor β

ASJC Scopus subject areas

  • Immunology

Cite this

Activation of Transforming Growth Factor β by Malaria Parasite-derived Metalloproteinases and a Thrombospondin-like Molecule. / Omer, Fakhreldin M.; De Souza, J. Brian; Corran, Patrick H.; Sultan, Ali; Riley, Eleanor M.

In: Journal of Experimental Medicine, Vol. 198, No. 12, 15.12.2003, p. 1817-1827.

Research output: Contribution to journalArticle

Omer, Fakhreldin M. ; De Souza, J. Brian ; Corran, Patrick H. ; Sultan, Ali ; Riley, Eleanor M. / Activation of Transforming Growth Factor β by Malaria Parasite-derived Metalloproteinases and a Thrombospondin-like Molecule. In: Journal of Experimental Medicine. 2003 ; Vol. 198, No. 12. pp. 1817-1827.
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