title: Dual engagement of the NLRP3 and AIM2 inflammasomes by plasmodium-derived hemozoin and DNA during malaria.
abstract: Hemozoin (Hz) is the crystalline detoxification product of hemoglobin in Plasmodium-infected erythrocytes. We previously proposed that Hz can carry plasmodial DNA into a subcellular compartment that is accessible to Toll-like receptor 9 (TLR9), inducing an inflammatory signal. Hz also activates the NLRP3 inflammasome in primed cells. We found that Hz appears to colocalize with DNA in infected erythrocytes, even before RBC rupture or phagolysosomal digestion. Using synthetic Hz coated in vitro with plasmodial genomic DNA (gDNA) or CpG oligodeoxynucleotides, 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 Plasmodium-infected RBCs. 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.
authors.affiliation: Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
authors.forename: Parisa
authors.initials: P
authors.lastname: Kalantari
authors.affiliation: Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
authors.forename: Rosane B
authors.initials: RB
authors.lastname: DeOliveira
authors.affiliation: Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
authors.forename: Jennie
authors.initials: J
authors.lastname: Chan
authors.affiliation: Dipartimento di Scienze Farmacologiche e Biomolecolari, Università Degli Studi di Milano, Via Pascal 36, Milano 20133, Italy.
authors.forename: Yolanda
authors.initials: Y
authors.lastname: Corbett
authors.affiliation: Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
authors.forename: Vijay
authors.initials: V
authors.lastname: Rathinam
authors.affiliation: Institute of Innate Immunity, Biomedical Center, 1G008, University Hospitals, University of Bonn, Sigmund-Freud-Strasse 25, Bonn 53127, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Stutz
authors.affiliation: Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, MA 01605, USA; Institute of Innate Immunity, Biomedical Center, 1G008, University Hospitals, University of Bonn, Sigmund-Freud-Strasse 25, Bonn 53127, Germany.
authors.forename: Eicke
authors.initials: E
authors.lastname: Latz
authors.affiliation: Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, MA 01605, USA; Department of Parasitology and Department of Biochemistry and Immunology, Biological Sciences Institute, Federal University of Minas Gerais, Avenida Antonio Carlos 6627, Belo Horizonte, MG 31270, Brazil.
authors.forename: Ricardo T
authors.initials: RT
authors.lastname: Gazzinelli
authors.affiliation: Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
authors.forename: Douglas T
authors.initials: DT
authors.lastname: Golenbock
authors.affiliation: Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, MA 01605, USA. Electronic address: kate.fitzgerald@umassmed.edu.
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Fitzgerald
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D016054:DNA, Protozoan / Q000378:metabolism* / Q000494:pharmacology; D004268:DNA-Binding Proteins; D004912:Erythrocytes / Q000187:drug effects / Q000378:metabolism / Q000469:parasitology; D006420:Hemeproteins / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D058847:Inflammasomes / Q000235:genetics / Q000378:metabolism*; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D008288:Malaria / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010587:Phagocytosis; D010961:Plasmodium / Q000472:pathogenicity; D051217:Toll-Like Receptor 9 / Q000378:metabolism
chemical_list: C540422:Aim2 protein, mouse; D002352:Carrier Proteins; D016054:DNA, Protozoan; D004268:DNA-Binding Proteins; D006420:Hemeproteins; D058847:Inflammasomes; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D009687:Nuclear Proteins; C495371:TLR9 protein, human; D051217:Toll-Like Receptor 9; C020753:hemozoin