gammadelta 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 TNF, IL-1 and 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 P. falciparum parasitised 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-1beta and MCP-2. TNF and MIP-1alpha were significantly higher in the SM compared to the UM group. IL-10, IL-6, MIP-1alpha, MIP-1beta 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-1beta and MIP-1alpha were produced predominantly by monocytes and gammadelta 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 gammadelta T cells. Monocyte-derived chemokines support a role for monocyte infiltrates in the aetiology of SM.