Abstract
Hepatocyte invasion by Plasmodium sporozoites represents a promising target for innovative antimalarial therapy, but the molecular events mediating this process are still largely uncharacterized. We previously showed that Plasmodium falciparum sporozoite entry into hepatocytes strictly requires CD81. However, CD81-overexpressing human hepatoma cells remain refractory to P. falciparum infection, suggesting the existence of additional host factors necessary for sporozoite entry. Here, through differential transcriptomic analysis of human hepatocytes and hepatoma HepG2-CD81 cells, the transmembrane protein Aquaporin-9 (AQP9) was found to be among the most downregulated genes in hepatoma cells. RNA silencing showed that sporozoite invasion of hepatocytes requires AQP9 expression. AQP9 overexpression in hepatocytes increased their permissiveness to P. falciparum. Moreover, chemical disruption with the AQP9 inhibitor phloretin markedly inhibited hepatocyte infection. Our findings identify AQP9 as a novel host factor required for P. falciparum sporozoite hepatocyte-entry and indicate that AQP9 could be a potential therapeutic target.
Highlights
Of the protozoan parasites of humans, Plasmodium falciparum is the deadliest, accounting for an estimated 228 million cases of malaria and causing 405 000 deaths in 2018 (WHO | World malaria report 2018)
Our results showed that a total of 276 genes were downregulated in nonpermissive hepatoma cells compared to the permissive hepatocytes, with human hepatocytes (HHs)/HC ratios higher than 3
Comparison of the transcriptome of human hepatocytes with that of human hepatoma HepG2-CD81 cells, which do not support P. falciparum sporozoite infection, led to identification of genes whose expression is downregulated in hepatoma cells
Summary
Of the protozoan parasites of humans, Plasmodium falciparum is the deadliest, accounting for an estimated 228 million cases of malaria and causing 405 000 deaths in 2018 (WHO | World malaria report 2018). After being inoculated in the skin of a host during the bite of an infected Anopheles mosquito, the sporozoite form of the parasite is quickly conveyed by the blood to the liver Once there, it is sequestered via interactions with heparan sulphate proteoglycans (HSPGs), crosses the Plasmodium hepatocyte Infection Requires AQP9 endothelial barrier, and migrates through several parenchymal cells before invading a hepatocyte by forming a membrane-bound compartment called the parasitophorous vacuole membrane (PVM), where it can develop and multiply to form merozoites that initiate the pathogenic erythrocytic cycle (Mota et al, 2001). Another host factor, aquaporin 3 (AQP3), which is a water and glycerol channel belonging to the aquaglyceroporin subfamily, has been implicated in the maturation of parasites after invasion (Posfai et al, 2018; Posfai et al, 2020)
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