Structural analysis of adhesion molecules involved in malaria pathogenesis.

Abstract

Malaria still remains a major global health problem infecting millions of people each year. The pathology associated with the disease is due to the cyclical invasion and destruction of the erythrocyte by the asexual stage of the parasite leading to anemia. In addition the sequestration of the infected erythrocyte to the endothelial cells of the capillaries can lead to obstruction of blood flow and is linked to severe malaria pathology like cerebral malaria. Both the efficient invasion of the erythrocyte as well as sequestration is mediated by a range of different parasite encoded adhesion molecules. As these adhesion molecules tend to be very large proteins one initial aim of the project was to identify new functional domains mediating adhesion for a set of invasion proteins termed reticulocyte binding protein homologues. These newly identified domains along with a number of known adhesion domains important for parasite sequestration where then to be functionally characterized with the ultimate goal to determine their structure. While there were a number of setbacks in relation to the structural analysis of the adhesion domain, there was significant progress in the identification of functional domains of the invasion proteins. In addition, this project led to the identification of a minimal region of the sequestration related CIDR domain that is able to induce cross protective antibodies. The identification of important regions/domains for both invasion as well as sequestration related parasite proteins are important findings for the development of new intervention strategies against the malaria parasite.