Danielle I Stanisic1, Julia Cutts2, Emily Eriksson3, Freya J I Fowkes4, Anna Rosanas-Urgell5, Peter Siba5, Moses Laman6, Timothy M E Davis7, Laurens Manning7, Ivo Mueller8, Louis Schofield9. 1. Division of Infection and Immunity, Walter and Eliza Hall Institute, Parkville, Victoria, Australia Papua New Guinea Institute of Medical Research, Madang, Papua New Guinea. 2. Division of Infection and Immunity, Walter and Eliza Hall Institute, Parkville, Victoria, Australia. 3. Division of Infection and Immunity, Walter and Eliza Hall Institute, Parkville, Victoria, Australia Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia. 4. Burnet Institute for Medical Research and Public Health, Prahan, Victoria, Australia. 5. Papua New Guinea Institute of Medical Research, Madang, Papua New Guinea. 6. 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. 7. School of Medicine and Pharmacology, University of Western Australia, Fremantle Hospital, Fremantle, Western Australia, Australia. 8. 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. 9. 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.
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.
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.
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