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2020-01-01
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DUAL ENGAGEMENT OF THE NLRP3 AND AIM2 INFLAMMASOMES BY PLASMODIUM-DERIVED HEMOZOIN AND DNA DURING MALARIA
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Division of Infectious Diseases and Immunology. University of Massachusetts Medical School.Worcester, MA, USA.
Division of Infectious Diseases and Immunology. University of Massachusetts Medical School.Worcester, MA, USA.
Division of Infectious Diseases and Immunology. University of Massachusetts Medical School.Worcester, MA, USA.
Dipartimento di Scienze Farmacologiche e Biomolecolari Universita Degli Studi di Milano. Milano, Italy.
Division of Infectious Diseases and Immunology. University of Massachusetts Medical School.Worcester, MA, USA.
Institute of Innate Immunity. Biomedical Center. University Hospitals. University of Bonn. Sigmund-Freud-Str. 25, Bonn 53127, Germany.
Division of Infectious Diseases and Immunology. University of Massachusetts Medical School.Worcester, MA, USA/Institute of Innate Immunity. Biomedical Center. University Hospitals. University of Bonn. Sigmund-Freud-Str. 25, Bonn 53127, Germany.
Division of Infectious Diseases and Immunology. University of Massachusetts Medical School.Worcester, MA, USA / Universidade Federal de Minas Gerais. Instituto de Ciências Biológicas. Departamento de Parasitologia e Departamento de Bioquímica e Imunologia. Belo Horizonte, MG, Brasil.
Division of Infectious Diseases and Immunology. University of Massachusetts Medical School.Worcester, MA, USA.
Division of Infectious Diseases and Immunology. University of Massachusetts Medical School.Worcester, MA, USA.
Division of Infectious Diseases and Immunology. University of Massachusetts Medical School.Worcester, MA, USA.
Division of Infectious Diseases and Immunology. University of Massachusetts Medical School.Worcester, MA, USA.
Division of Infectious Diseases and Immunology. University of Massachusetts Medical School.Worcester, MA, USA.
Dipartimento di Scienze Farmacologiche e Biomolecolari Universita Degli Studi di Milano. Milano, Italy.
Division of Infectious Diseases and Immunology. University of Massachusetts Medical School.Worcester, MA, USA.
Institute of Innate Immunity. Biomedical Center. University Hospitals. University of Bonn. Sigmund-Freud-Str. 25, Bonn 53127, Germany.
Division of Infectious Diseases and Immunology. University of Massachusetts Medical School.Worcester, MA, USA/Institute of Innate Immunity. Biomedical Center. University Hospitals. University of Bonn. Sigmund-Freud-Str. 25, Bonn 53127, Germany.
Division of Infectious Diseases and Immunology. University of Massachusetts Medical School.Worcester, MA, USA / Universidade Federal de Minas Gerais. Instituto de Ciências Biológicas. Departamento de Parasitologia e Departamento de Bioquímica e Imunologia. Belo Horizonte, MG, Brasil.
Division of Infectious Diseases and Immunology. University of Massachusetts Medical School.Worcester, MA, USA.
Division of Infectious Diseases and Immunology. University of Massachusetts Medical School.Worcester, MA, USA.
Division of Infectious Diseases and Immunology. University of Massachusetts Medical School.Worcester, MA, USA.
Abstract
Hemozoin (Hz) is the crystalline detoxification product of hemoglobin in plasmodial-infected erythrocytes. We previously proposed that Hz can carry plasmodial DNA into a subcellular compartment accessible to Toll-like receptor 9 (TLR9), inducing an inflammatory signal. Hemozoin also activates the NLRP3 inflammasome in primed cells. We found that Hz appears to co localize with DNA in infected erythrocytes, even prior to RBC rupture or phagolysosomal digestion. Using synthetic Hz coated in vitro with plasmodial genomic DNA (gDNA) or CpG-oligonucleotides, we observed that DNA-complexed Hz induced TLR9 translocation, providing a priming and an activation signal for inflammasomes. After phagocytosis, Hz and DNA dissociate. Hz subsequently induces phagolysosomal destabilization, allowing phagolysosomal contents access to the cytosol where DNA receptors become activated. Similar observations were made with plasmodial-infected RBC. Finally, infected erythrocytes activated both the NLRP3 and AIM2 inflammasomes. These observations suggest that Hz and DNA work together to induce systemic inflammation during malaria.
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