γδ T Cells and CD14+ Monocytes Are Predominant Cellular Sources of Cytokines and Chemokines Associated With Severe Malaria

J Infect Dis. 2014 Jul 15;210(2):295-305. doi: 10.1093/infdis/jiu083. Epub 2014 Feb 12.

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.

Keywords: chemokines; cytokines; monocyte/macrophages; severe malaria; γδ T cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Case-Control Studies
  • Child
  • Child, Preschool
  • Cytokines / metabolism*
  • Female
  • Humans
  • Infant
  • Lipopolysaccharide Receptors / analysis
  • Malaria, Falciparum / immunology*
  • Male
  • Monocytes / chemistry
  • Monocytes / immunology*
  • Papua New Guinea
  • Plasmodium falciparum / immunology*
  • Receptors, Antigen, T-Cell, gamma-delta / analysis
  • T-Lymphocytes / chemistry
  • T-Lymphocytes / immunology*

Substances

  • Cytokines
  • Lipopolysaccharide Receptors
  • Receptors, Antigen, T-Cell, gamma-delta