Plasmodium Circumsporozoite Protein Promotes the Development of the Liver Stages of the Parasite

The liver stages of malaria sporozoites develop in the hepatocyte cytoplasm inside a parasitophorous vacuole (PV). The circumsporozoite (CS) protein, the major surface protein of sporozoites, traverses the PV membrane and enters the cytoplasm and nucleus of hepatocytes. CS export into the cytoplasm requires the presence of pexel/VTS motifs. The transport of CS into the host nucleus is then mediated by importin (Imp) alpha3/beta1 that binds to the nuclear localization signal of CS localized in the conserved region II-plus. The NLSs of CS and of NFkB p50 share the same Imp. The entry of NFkB p50 into the nucleus is strongly inhibited in cell lines expressing CS, and in infected hepatocytes. Micro-array data from CS expressing cell line shows that 40 NFkB targets were significantly down regulated. Among them inflammation related MIP3a and PTGS transcripts were 65 and 22 fold down regulated, thus explaining the notable absence of inflammatory cells surrounding exo-erythrocytic forms (EEFs). The presence of CS in the cytoplasm of hepatocytes enhances EEF growth both in vitro and in vivo. Therefore Plasmodium blood stages and EEFs use the same strategy to secrete proteins into the cytoplasm of host cells and remodel it to the parasites advantage.

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Singh AP, Buscaglia CA, Wang Q, Levay A, Nussenzweig DR, Walker JR, Winzeler EA, Fujii H, Fontoura BM, Nussenzweig V