Malaria hemozoin is immunologically inert but radically enhances innate responses by presenting malaria DNA to Toll-like receptor 9
Department of Medicine, Division of Infectious Diseases and Immunology
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
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 contain <1 microg of malarial>DNA; 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.
DOI of Published Version
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
Proceedings of the National Academy of Sciences of the United States of America
Parroche, Peggy; Lauw, 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.; and Golenbock, Douglas, "Malaria hemozoin is immunologically inert but radically enhances innate responses by presenting malaria DNA to Toll-like receptor 9" (2007). Open Access Articles. 1359.