The innate immune response and human severe malaria

© 2011 Dr. Julia C. CuttsMalaria remains a major cause of morbidity and mortality throughout the tropical world. The emergence of parasite strains resistant to chloroquine and other commonly used anti-malarial drugs provides an urgent call for vaccine development and novel drug discovery. The clinical manifestations of a P. falciparum infection can range from a mild febrile illness to life-threatening severe malaria, however the determinants of disease severity are not well understood. Although the early, innate immune response to malaria serves to limit parasite growth and reduce clinical manifestations, endogenous mediators produced in response to bioactive parasite products may contribute to pathology associated with malaria. The P. falciparum glycosylphosphatidylinositol (GPI) anchor has been described as a malarial toxin, capable of stimulating pro-inflammatory cytokine responses in vitro and in vivo. Vaccination with a synthetic form of the GPI glycan protects mice from experimental cerebral malaria and death. However attempts to investigate the bioactivity of GPI have been hindered by a lack of suitable reagents for its study. Monoclonal antibodies were raised to P. falciparum GPI and used as probes to investigate the role of GPI in parasite cell biology. The expression of free GPI in late schizonts, dynamic localization of GPI during merozoite invasion, and growth inhibition in the presence of an anti-GPI monoclonal antibody suggest that GPI may have a role in invasion of erythrocytes. Furthermore, the pan-species and multiple life stage reactivity of anti-GPI antibodies have important implications for vaccine development. The second part of this thesis describes a study of cellular cytokine and chemokine responses in a severe malaria case control study in Papua New Guinean children. Cytokines and chemokines produced by convalescent peripheral blood mononuclear cells (PBMC) in response to stimulation with parasitized red blood cells or Toll-like receptor 2 (TLR2) and TLR4 agonists were significantly associated with severe malaria. A more comprehensive understanding of the role of these endogenous mediators in malaria pathogenesis will aid in the development of effective vaccines and may provide the opportunity for novel interventions