γδ T cells and CD14+ monocytes are predominant cellular sources of cytokines and chemokines associated with severe malaria

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.