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2024
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MALARIA HEMOZOIN IS IMMUNOLOGICALLY INERT BUT RADICALLY ENHANCES INNATE RESPONSES BY PRESENTING MALARIA DNA TO TOLL-LIKE RECEPTOR 9
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University of Massachusetts Medical School. Division of Infectious Diseases and Immunology. Worcester, MA, United States of America.
University of Massachusetts Medical School. Division of Infectious Diseases and Immunology. Worcester, MA, United States of America.
University of Massachusetts Medical School. Division of Infectious Diseases and Immunology. Worcester, MA, United States of America.
University of Massachusetts Medical School. Division of Infectious Diseases and Immunology. Worcester, MA, United States of America.
University of Massachusetts Medical School. Division of Infectious Diseases and Immunology. Worcester, MA, United States of America.
University of Massachusetts Medical School. Division of Infectious Diseases and Immunology. Worcester, MA, United States of America.
University of Massachusetts Medical School. Division of Infectious Diseases and Immunology. Worcester, MA, United States of America.
Eisai Research Institute. Andover, MA, United States of America.
McGill University. Department of Microbiology/Immunology.Montreal, Quebec, Canada
Federal University of Minas Gerais.Biological Sciences Institute. Department of Biochemistry and Immunology and Department of Parasitology. Belo Horizonte, MG, Brazil
Centro de Pesquisas Rene Rachou.Fundação Oswaldo Cruz. Belo Horizonte, MG, Brazil/Federal University of Minas Gerais.Biological Sciences Institute. Department of Biochemistry and Immunology and Department of Parasitology. Belo Horizonte, MG, Brazil
University of Massachusetts Medical School. Division of Infectious Diseases and Immunology. Worcester, MA, United States of America/Centro de Pesquisas Rene Rachou.Fundação Oswaldo Cruz. Belo Horizonte, MG, Brazil
University of Massachusetts Medical School. Division of Infectious Diseases and Immunology. Worcester, MA, United States of America.
University of Massachusetts Medical School. Division of Infectious Diseases and Immunology. Worcester, MA, United States of America.
University of Massachusetts Medical School. Division of Infectious Diseases and Immunology. Worcester, MA, United States of America.
University of Massachusetts Medical School. Division of Infectious Diseases and Immunology. Worcester, MA, United States of America.
University of Massachusetts Medical School. Division of Infectious Diseases and Immunology. Worcester, MA, United States of America.
University of Massachusetts Medical School. Division of Infectious Diseases and Immunology. Worcester, MA, United States of America.
Eisai Research Institute. Andover, MA, United States of America.
McGill University. Department of Microbiology/Immunology.Montreal, Quebec, Canada
Federal University of Minas Gerais.Biological Sciences Institute. Department of Biochemistry and Immunology and Department of Parasitology. Belo Horizonte, MG, Brazil
Centro de Pesquisas Rene Rachou.Fundação Oswaldo Cruz. Belo Horizonte, MG, Brazil/Federal University of Minas Gerais.Biological Sciences Institute. Department of Biochemistry and Immunology and Department of Parasitology. Belo Horizonte, MG, Brazil
University of Massachusetts Medical School. Division of Infectious Diseases and Immunology. Worcester, MA, United States of America/Centro de Pesquisas Rene Rachou.Fundação Oswaldo Cruz. Belo Horizonte, MG, Brazil
Abstract in Portuguese
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 (P-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 TILR9 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 mu g 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 proinfiammatory, 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
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