Stanisic, Danielle I., Cutts, Julia, Eriksson, Emily, Fowkes, Freya J.I., Rosanas-Urgell, Anna, Siba, Peter, Laman, Moses, Davis, Timothy M.E., Manning, Laurens, Mueller, Ivo, and Schofield, Louis (2014) γδT cells and CD14(+) monocytes are predominant cellular sources of cytokines and chemokines associated with severe malaria. Journal of Infectious Diseases, 210 (2). pp. 295-305.

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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-1 beta m and MCP-2. TNF and MIP-1 α were significantly higher in the SM compared to the UM group. IL-10, IL-6, MIP-1 α, MIP-1 β, 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-1 β, and MIP-1 α 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 gamma delta T cells. Monocyte-derived chemokines support a role for monocyte infiltrates in the etiology of SM.

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