Infection of the liver by Plasmodium parasites, the causative agents of malaria, is an essential and clinically silent phase that constitutes an ideal target for anti-malarial prophylactic approaches such as vaccines. After inoculation in the skin by a mosquito, Plasmodium sporozoites migrate to the liver and invade hepatocytes, where they differentiate into liver stages and thousands of pathogenic merozoites. Liver stage-infected hepatocytes are potential targets for protective CD8 T cells elicited after immunization with live attenuated sporozoites, but the target antigens remain to be identified. We have previously identified a master regulator of Plasmodium liver stage development, named SLARP, which regulates gene expression during parasite stage conversion. SLARP-deficient parasites show a complete developmental arrest in the liver and, interestingly, confer poor protective immunity in rodent malaria models. We have recently generated a list of genes that are regulated by SLARP and may be involved in liver stage development and protective immunity. The objectives of this proposal are 1) to use a medium throughput reverse genetics approach to analyze the role of these genes during stage conversion, and 2) to investigate the molecular basis of SLARP-dependent gene regulation. One major roadblock for the development of pre-erythrocytic immune intervention strategies is the remodeling of the parasite antigenic make-up during stage conversion upon host switch. Generation of parasite lines with defined defects in stage conversion, ranging from early transformation to onset of DNA replication and parasite growth, will aid in prioritizing candidate protective antigens, which together can elicit lasting protection against reinfection. Furthermore, a better understanding at the molecular level of the process of parasite differentiation in the liver is a pre-requisite for the rational development of novel therapeutic approaches targeting malaria pre-erythrocytic stages.
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