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Regulation of Puf2 Expression is Critical for Plasmodium Sporozoite Development and Maintenance of Sporozoite Transmissibility

ABSTRACT: Malaria’s cycle of infection requires parasite transmission between a mosquito vector and a vertebrate host. Plasmodium regulates transmission by translationally repressing specific mRNAs until their products are needed. We demonstrate that the Plasmodium yoelii Pumilio-FBF family member Puf2 allows the sporozoite to retain its infectivity in the mosquito salivary glands while awaiting transmission. Puf2 mediates this critical feature solely through its RNA-Binding Domain (RBD) likely by protecting and silencing specific mRNAs. Puf2 storage granules are distinct from stress granules and P-bodies and dissolve rapidly after infection of hepatocytes, likely releasing the protected and silenced transcripts for ‘just-in-time’ translation by early exoerythrocytic forms (EEFs). Further corroborating this model, pypuf2- sporozoites have no apparent defect in host infection early after invading the salivary glands, but become progressively noninfectious and subsequently prematurely transform into EEFs during prolonged salivary gland residence. In contrast, the premature overexpression of Puf2 in oocysts causes striking deregulation of sporozoite maturation, resulting in fewer oocyst sporozoites that are non-infectious and unable to colonize the salivary glands. Maintenance of Puf2 expression in liver stage parasites produces no phenotype, suggesting that a window of permissive expression exists. Finally, by conducting the first comparative RNAseq analysis of Plasmodium sporozoites, we have uncovered that Puf2 may play a role in both the protection of specific transcripts as well as RNA turnover via the CCR4/Not complex. These findings uncover requirements for maintaining a window of opportunity for the malaria parasite to accommodate the unpredictable moment of transmission from mosquito to vertebrate host.

ORGANISM(S): Plasmodium yoelii yoelii 17XNL

PROVIDER: GSE41873 | GEO | 2012/10/27

SECONDARY ACCESSION(S): PRJNA178363

REPOSITORIES: GEO

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Project description:Simultaneous analysis of Plasmodium falciparum and Anopheles gambiae gene expression: an assessment of parasite maturation and of the mosquito response to infection. Malaria is probably the most lethal and most prevalent parasitic disease in the world, causing more than one million deaths per year. In spite of intensive research, no vaccine exists and good vaccine candidates are still a necessity. Plasmodium sporozoites from mosquito midguts are not as infective as those from salivary glands, presenting a different type of motility which is presumably associated with their invasive capacity. It is assumed that these differences are due to maturation of sporozoites, which happens either in the salivary glands or somewhere along the way from the midgut to the glands. Indeed, the invasion of the salivary gland is considered to be an essential step for malaria transmission to the host and it is known to causes expression of multiple genes in the parasite and activation of some immune-response genes in the insect. Here we compared the gene expression profile of P. falciparum parasites from midgut and salivary glands in order to search for genes involved in parasite maturation; on the assumption that any differentially expressed genes found under this condition could be potentially related to the higher infectivity of the salivary gland derived sporozoites and therefore would be potentially good vaccine candidates. Also, because very little is known about mosquito genes involved in the response to Plasmodium, we compared the gene expression profile of infected and uninfected midguts and salivary glands. Our results demonstrate that, upon infection, at least 13 genes are differentially expressed in the mosquito midgut and 43 in the salivary gland. Gene ontology enrichment analysis showed that among other things, in mosquito salivary glands, infection causes multiple genes related to chitin metabolism to be differentially expressed. Also and more importantly, at least 54 genes were differentially expressed in P. falciparum from salivary glands in comparison to midgut (19 down-regulated and 35 up-regulated). Last, we show for the first time that P. falciparum causes multiple genes in the salivary gland to be regulated and that some of those genes could be potentially beneficial to the parasite.

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Regulation of Puf2 Expression is Critical for Plasmodium Sporozoite Development and Maintenance of Sporozoite Transmissibility

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