Abstract
The molecular biology of the clinically silent pre-erythrocytic stages of mammalian Plasmodium spp, composed of both the sporozoite and liver stages, has remained largely uncharacterized. Improved understanding of the biological processes required for progression through the pre-erythrocytic stages could lead to the identification of novel drug and vaccine targets. To gain insights into the molecular events that occur during the pre-erythrocytic stages of Plasmodium, comparative transcriptional analysis was performed on radiation attenuated sporozoites (RAS), wild type sporozoites (wtSPZ) and liver stage parasites collected either 24 hours (24hrLS) or 48 hours (48hrLS) after mice were infected with Plasmodium yoelii. Our results revealed 1100 Plasmodium genes that were differentially expressed in one or more constituents of the pre-erythrocytic stages relative to the mixed blood stages. Overall, the transcriptional profile of P. yoelii gradually became more similar to the mixed blood stages as pre-erythrocytic stage development progressed into the mature liver stage schizont. The transcriptional profiles of RAS and wtSPZ were found to be nearly identical. Likewise, the transcriptional profile of 24hrLS was very similar to that of the 48hrLS parasites. The largest differences in gene expression were observed when comparing wtSPZ or RAS to either of the liver stage samples. Further characterization of the differentially expressed genes identified in this study could help elucidate the biological mechanisms employed by Plasmodium during the pre-erythrocytic stages.
Highlights
Malaria, caused by hematoprotozoan parasites of the genus Plasmodium, remains a global health crisis with high annual morbidity and mortality
Microarray analysis To develop a better understanding of the dynamics of the molecular processes occurring during the pre-erythrocytic stages of Plasmodium we performed a microarray based analysis of the transcriptional profile of wild type salivary gland sporozoites, radiation attenuated sporozoites (RAS), and liver stage parasites collected from mice livers 24 hours (24hrLS) and 48 hours (48hrLS) after wild type sporozoites (wtSPZ) infection, using the P. yoelii (17XNL) rodent malaria model
A reference design was chosen to allow comparisons to be made between pre-erythrocytic RNA samples hybridized at different times to oligonucleotide arrays which were designed using the genome of P. yoelii
Summary
Malaria, caused by hematoprotozoan parasites of the genus Plasmodium, remains a global health crisis with high annual morbidity and mortality. The malaria infection is initiated after Plasmodium sporozoites are injected of into the skin during the taking of a blood meal by Anopheles mosquitoes. The sporozoites migrate to the liver, invade host hepatocytes, and develop into trophozoites. After a period of growth and several rounds of asexual replication, the parasite transitions into mature liver stage schizonts which contain thousands of infectious merozoites. The pre-erythrocytic stages of Plasmodium, which consist of the sporozoite and liver stages, represent the first opportunity the mammalian host has to mount a defense against Plasmodium infection. In malaria endemic areas, in which frequent exposure to Plasmodium sporozoites occur, immune responses directed at these parasite stages are weak, if at all detected [1,2]
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