Activation of transforming growth factor beta by malaria parasite-derived metalloproteinases and a thrombospondin-like molecule. Academic Article uri icon

Overview

abstract

  • 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.

publication date

  • December 15, 2003

Research

keywords

  • Metalloproteases
  • Plasmodium
  • Protozoan Proteins
  • Thrombospondin 1
  • Transforming Growth Factor beta

Identity

PubMed Central ID

  • PMC2194152

Scopus Document Identifier

  • 0348223800

Digital Object Identifier (DOI)

  • 10.1084/jem.20030713

PubMed ID

  • 14676296

Additional Document Info

volume

  • 198

issue

  • 12