title: γδ T cells and CD14+ monocytes are predominant cellular sources of cytokines and chemokines associated with severe malaria.
abstract: BACKGROUND
  Severe malaria (SM) is associated with high levels of cytokines such as tumor necrosis factor (TNF), interleukin 1 (IL-1), and interleukin 6 (IL-6). The role of chemokines is less clear, as is their cellular source.
  
  
  METHODS
  In a case-control study of children with SM (n = 200), uncomplicated malaria (UM) (n = 153) and healthy community controls (HC) (n = 162) in Papua, New Guinea, we measured cytokine/chemokine production by peripheral blood mononuclear cells (PBMCs) stimulated with live Plasmodium falciparum parasitized red blood cells (pRBC). Cellular sources were determined. Associations between immunological endpoints and clinical/parasitological variables were tested.
  
  
  RESULTS
  Compared to HC and UM, children with SM produced significantly higher IL-10, IP-10, MIP-1βm and MCP-2. TNF and MIP-1α were significantly higher in the SM compared to the UM group. IL-10, IL-6, MIP-1α, MIP-1β, and MCP-2 were associated with increased odds of SM. SM syndromes were associated with distinct cytokine/chemokine response profiles compared to UM cases. TNF, MIP-1β, and MIP-1α were produced predominantly by monocytes and γδ T cells, and IL-10 by CD4(+) T cells.
  
  
  CONCLUSIONS
  Early/innate PBMC responses to pRBC in vitro are informative as to cytokines/chemokines associated with SM. Predominant cellular sources are monocytes and γδ T cells. Monocyte-derived chemokines support a role for monocyte infiltrates in the etiology of SM.
authors: Division of Infection and Immunity, Walter and Eliza Hall Institute, Parkville, Victoria, Australia Papua New Guinea Institute of Medical Research, Madang, Papua New Guinea.
authors: Danielle I
authors: DI
authors: Stanisic
authors: Division of Infection and Immunity, Walter and Eliza Hall Institute, Parkville, Victoria, Australia.
authors: Julia
authors: J
authors: Cutts
authors: Division of Infection and Immunity, Walter and Eliza Hall Institute, Parkville, Victoria, Australia Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.
authors: Emily
authors: E
authors: Eriksson
authors: Burnet Institute for Medical Research and Public Health, Prahan, Victoria, Australia.
authors: Freya J I
authors: FJ
authors: Fowkes
authors: Papua New Guinea Institute of Medical Research, Madang, Papua New Guinea.
authors: Anna
authors: A
authors: Rosanas-Urgell
authors: Papua New Guinea Institute of Medical Research, Madang, Papua New Guinea.
authors: Peter
authors: P
authors: Siba
authors: Papua New Guinea Institute of Medical Research, Madang, Papua New Guinea School of Medicine and Pharmacology, University of Western Australia, Fremantle Hospital, Fremantle, Western Australia, Australia.
authors: Moses
authors: M
authors: Laman
authors: School of Medicine and Pharmacology, University of Western Australia, Fremantle Hospital, Fremantle, Western Australia, Australia.
authors: Timothy M E
authors: TM
authors: Davis
authors: School of Medicine and Pharmacology, University of Western Australia, Fremantle Hospital, Fremantle, Western Australia, Australia.
authors: Laurens
authors: L
authors: Manning
authors: Division of Infection and Immunity, Walter and Eliza Hall Institute, Parkville, Victoria, Australia Papua New Guinea Institute of Medical Research, Madang, Papua New Guinea Center de Recerca en Salut Internacional de Barcelona (CRESIB), Barcelona, Spain.
authors: Ivo
authors: I
authors: Mueller
authors: Division of Infection and Immunity, Walter and Eliza Hall Institute, Parkville, Victoria, Australia Australian Institute of Tropical Health and Medicine, James Cook University, Queensland, Australia.
authors: Louis
authors: L
authors: Schofield
mesh_terms: D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D016207:Cytokines / Q000378:metabolism*; D005260:Female; D006801:Humans; D007223:Infant; D018950:Lipopolysaccharide Receptors / Q000032:analysis; D016778:Malaria, Falciparum / Q000276:immunology*; D008297:Male; D009000:Monocytes / Q000737:chemistry / Q000276:immunology*; D010219:Papua New Guinea; D010963:Plasmodium falciparum / Q000276:immunology*; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000032:analysis; D013601:T-Lymphocytes / Q000737:chemistry / Q000276:immunology*
chemical_list: D016207:Cytokines; D018950:Lipopolysaccharide Receptors; D016692:Receptors, Antigen, T-Cell, gamma-delta
keywords: chemokines; cytokines; monocyte/macrophages; severe malaria; γδ T cells