title: DNA-Containing Immunocomplexes Promote Inflammasome Assembly and Release of Pyrogenic Cytokines by CD14+ CD16+ CD64high CD32low Inflammatory Monocytes from Malaria Patients.
abstract: High levels of circulating immunocomplexes (ICs) are found in patients with either infectious or sterile inflammation. We report that patients with either Plasmodium falciparum or Plasmodium vivax malaria have increased levels of circulating anti-DNA antibodies and ICs containing parasite DNA. Upon stimulation with malaria-induced ICs, monocytes express an NF-κB transcriptional signature. The main source of IC-induced proinflammatory cytokines (i.e., tumor necrosis factor alpha [TNF-α] and interleukin-1β [IL-1β])in peripheral blood mononuclear cells from acute malaria patients was found to be a CD14(+) CD16 (FcγRIIIA)(+) CD64 (FcγRI)(high) CD32 (FcγRIIB)(low) monocyte subset. Monocytes from convalescent patients were predominantly of the classical phenotype (CD14(+) CD16(-)) that produces high levels of IL-10 and lower levels of TNF-α and IL-1β in response to ICs. Finally, we report a novel role for the proinflammatory activity of ICs by demonstrating their ability to induce inflammasome assembly and caspase-1 activation in human monocytes. These findings illuminate our understanding of the pathogenic role of ICs and monocyte subsets and may be relevant for future development of immunity-based interventions with broad applications to systemic inflammatory diseases.
  
  
  OBJECTIVE
  Every year, there are approximately 200 million cases of Plasmodium falciparum and P. vivax malaria, resulting in nearly 1 million deaths, most of which are children. Decades of research on malaria pathogenesis have established that the clinical manifestations are often a consequence of the systemic inflammation elicited by the parasite. Recent studies indicate that parasite DNA is a main proinflammatory component during infection with different Plasmodium species. This finding resembles the mechanism of disease in systemic lupus erythematosus, where host DNA plays a central role in stimulating an inflammatory process and self-damaging reactions. In this study, we disclose the mechanism by which ICs containing Plasmodium DNA activate innate immune cells and consequently stimulate systemic inflammation during acute episodes of malaria. Our results further suggest that Toll-like receptors and inflammasomes have a central role in malaria pathogenesis and provide new insights toward developing novel therapeutic interventions for this devastating disease.
authors.affiliation: Centro de Pesquisa René Rachou, Fundação Oswaldo Cruz, Belo Horizonte, Minas Gerais, Brazil.
authors.forename: Isabella C
authors.initials: IC
authors.lastname: Hirako
authors.affiliation: Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, Massachusetts, USA Centro Internacional de Entrenamiento e Investigaciones Medicas-CIDEIM, Cali, Colombia.
authors.forename: Carolina
authors.initials: C
authors.lastname: Gallego-Marin
authors.affiliation: Centro de Pesquisa René Rachou, Fundação Oswaldo Cruz, Belo Horizonte, Minas Gerais, Brazil Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.
authors.forename: Marco A
authors.initials: MA
authors.lastname: Ataide
authors.affiliation: Centro de Pesquisa René Rachou, Fundação Oswaldo Cruz, Belo Horizonte, Minas Gerais, Brazil Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors.forename: Warrison A
authors.initials: WA
authors.lastname: Andrade
authors.affiliation: Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.
authors.forename: Humberto
authors.initials: H
authors.lastname: Gravina
authors.affiliation: Centro de Pesquisa René Rachou, Fundação Oswaldo Cruz, Belo Horizonte, Minas Gerais, Brazil Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.
authors.forename: Bruno C
authors.initials: BC
authors.lastname: Rocha
authors.affiliation: Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors.forename: Rosane B
authors.initials: RB
authors.lastname: de Oliveira
authors.affiliation: Centro de Pesquisa em Medicina Tropical, Porto Velho, Rondônia, Brazil.
authors.forename: Dhelio B
authors.initials: DB
authors.lastname: Pereira
authors.affiliation: School of Medicine, University of California San Diego, San Diego, California, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Vinetz
authors.affiliation: Center for Autoimmune and Musculoskeletal Diseases, The Feinstein Institute for Medical Research, Manhasset, New York, USA.
authors.forename: Betty
authors.initials: B
authors.lastname: Diamond
authors.affiliation: Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors.forename: Sanjay
authors.initials: S
authors.lastname: Ram
authors.affiliation: Centro de Pesquisa René Rachou, Fundação Oswaldo Cruz, Belo Horizonte, Minas Gerais, Brazil Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors.forename: Douglas T
authors.initials: DT
authors.lastname: Golenbock
authors.affiliation: Centro de Pesquisa René Rachou, Fundação Oswaldo Cruz, Belo Horizonte, Minas Gerais, Brazil Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, Massachusetts, USA Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil ricardo.gazzinelli@umassmed.edu.
authors.forename: Ricardo T
authors.initials: RT
authors.lastname: Gazzinelli
mesh_terms: D000936:Antigen-Antibody Complex / Q000097:blood / Q000378:metabolism*; D015703:Antigens, CD / Q000032:analysis; D016207:Cytokines / Q000378:metabolism*; D016054:DNA, Protozoan / Q000276:immunology*; D006801:Humans; D016130:Immunophenotyping; D058847:Inflammasomes / Q000378:metabolism*; D016778:Malaria, Falciparum / Q000276:immunology / Q000473:pathology*; D016780:Malaria, Vivax / Q000276:immunology / Q000473:pathology*; D009000:Monocytes / Q000737:chemistry / Q000378:metabolism*; D055503:Protein Multimerization
chemical_list: D000936:Antigen-Antibody Complex; D015703:Antigens, CD; D016207:Cytokines; D016054:DNA, Protozoan; D058847:Inflammasomes