Malaria hemozoin is immunologically inert but radically enhances innate responses by presenting malaria DNA to Toll-like receptor 9
Authors
Parroche, PeggyLauw, Fanny N.
Goutagny, Nadege
Latz, Eicke
Monks, Brian G.
Visintin, Alberto
Halmen, Kristen A.
Lamphier, Marc S.
Olivier, Martin
Bartholomeu, Daniella C.
Gazzinelli, Ricardo T.
Golenbock, Douglas
UMass Chan Affiliations
Department of Medicine, Division of Infectious Diseases and ImmunologyDocument Type
Journal ArticlePublication Date
2007-01-31Keywords
Animals*Antigen Presentation
DNA, Protozoan
Hemeproteins
Humans
*Immunity, Natural
Lymphocyte Activation
Melanoma, Experimental
Mice
Plasmodium falciparum
Toll-Like Receptor 9
Life Sciences
Medicine and Health Sciences
Metadata
Show full item recordAbstract
Hemozoin (HZ) is an insoluble crystal formed in the food vacuole of malaria parasites. HZ has been reported to induce inflammation by directly engaging Toll-like receptor (TLR) 9, an endosomal receptor. "Synthetic" HZ (beta-hematin), typically generated from partially purified extracts of bovine hemin, is structurally identical to natural HZ. When HPLC-purified hemin was used to synthesize the crystal, beta-hematin had no inflammatory activity. In contrast, natural HZ from Plasmodium falciparum cultures was a potent TLR9 inducer. Natural HZ bound recombinant TLR9 ectodomain, but not TLR2. Both TLR9 stimulation and TLR9 binding of HZ were abolished by nuclease treatment. PCR analysis demonstrated that natural HZ is coated with malarial but not human DNA. Purified malarial DNA activated TLR9 but only when DNA was targeted directly to the endosome with a transfection reagent. Stimulatory quantities of natural HZ containDNA; its potency in activating immune responses was even greater than transfecting malarial DNA. Thus, although the malarial genome is extremely AT-rich, its DNA is highly proinflammatory, with the potential to induce cytokinemia and fever during disease. However, its activity depends on being bound to HZ, which we propose amplifies the biological responses to malaria DNA by targeting it to a TLR9(+) intracellular compartment.Source
Proc Natl Acad Sci U S A. 2007 Feb 6;104(6):1919-24. Epub 2007 Jan 29. Link to article on publisher's site
DOI
10.1073/pnas.0608745104Permanent Link to this Item
http://hdl.handle.net/20.500.14038/38486PubMed ID
17261807Related Resources
ae974a485f413a2113503eed53cd6c53
10.1073/pnas.0608745104