γδ T cells and CD14+ Monocytes Are Predominant Cellular Sources of Cytokines and Chemokines Associated With Severe Malaria
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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-1߭ and MCP-2. TNF and MIP-1a were significantly higher in the SM compared to the UM group. IL-10, IL-6, MIP-1a, MIP-1߬ 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-1߬ and MIP-1a were produced predominantly by monocytes and ?d 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 ?d T cells. Monocyte-derived chemokines support a role for monocyte infiltrates in the etiology of SM.
Journal of Infectious Diseases