Study of Factors Involved in Resistance to Severe Malaria
Condition: Malaria
MeSH terms: Malaria
Study type: Observational

Summary: 
      This study will examine whether resistance to severe malaria is associated with weakening of
      a specific immune response (TLR-mediated pro-inflammatory cytokine response). Some children
      with mild malaria go on to develop severe disease, while others do not. The study will
      analyze certain substances in the blood to try to determine what factors may protect against
      severe malaria.

      Healthy children and children 3 - 10 years of age with severe malaria who are being treated
      at l'H pital Gabriel Toure in Mamako, Mali, West Africa, may be eligible for this study.
      Participants have a mall sample of blood drawn from a vein and from two finger pricks.
    

Detailed description: 
      Malaria remains an important public health threat, responsible for over two million deaths
      annually, the majority among African children. The mechanisms underlying resistance to the
      most severe manifestations of malaria remain elusive. Severe malaria has been associated with
      high levels of pro-inflammatory cytokines that may contribute to the pathogenesis of cerebral
      malaria, severe anemia and acidosis. This response is thought to be driven primarily by
      glycosylphosphatidylinositol (GPI) anchors derived from erythrocyte-stage Plasmodium
      falciparum. It has been suggested that antibodies against GPI are responsible for resistance
      to severe malaria, which has led to efforts to develop a GPI-based vaccine. An alternative
      explanation for the development of resistance to severe malaria is down regulation of the
      innate pro-inflammatory response by repeated ligation of toll-like receptors (TLR) by GPI, or
      other putative P. falciparum-derived TLR ligands, such as hemozoin. This cross-sectional
      study at l'Hopital Gabriel Toure in Bamako, Mali, proposes to test the hypothesis that
      resistance to severe malaria is associated with an attenuation of the TLR-mediated
      pro-inflammatory cytokine response. After informed consent is obtained from the participant's
      parent or guardian, 2-3 mL of venous blood will be drawn from each of 60 children: 40
      children presenting with acute P. falciparum infection (20 severe and 20 uncomplicated) and
      20 healthy, P. falciparum uninfected controls. The blood will be tested for antibody titers
      against GPI and Merozoite Surface Protein-1 (MSP-1). Peripheral blood mononuclear cells
      (PBMCs) will be isolated and cultured with GPI, hemozoin, lipoteichoic acid (LTA),
      lipopolysaccharide (LPS), and cytosine-guanine dinucleotide (CpG). At 24 hours, supernatant
      will be collected and the following cytokines measured: IL-1, IL-6, IL-8, IL-10, IL-12, and
      TNF-alpha. A clearer understanding of the responsiveness to TLR ligands in children from
      malaria endemic areas may provide information on potential intervention strategies such as
      GPI-based vaccines or the use of TLR agonists as vaccine adjuvants.
    

Keywords: Children; Cross-Sectional; Glycosylphosphatidylinositol; Cytokines; Peripheral Blood Mononuclear Cells; Malaria