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Plasmodium berghei PbeIK2KO sporozoites

ABSTRACT: Malaria sporozoites, the form transmitted by mosquitoes, are quiescent while in the insect salivary glands. It is only after the sporozoites are deposited in the host’s skin, migrate to the liver and infect hepatocytes that the parasites continue the life cycle. We show that the sporozoite latency is an active process that requires phosphorylation of the eukaryotic initiation factor-2α (eIF2α) by a sporozoite-specific kinase. Inactivation of the kinase gene leads to an overall enhancement of protein synthesis including of silenced liver stage proteins, and inhibits transmission of malaria. Specific inhibition of the eIF2α phosphatase by salubrinal has the opposite effect. Thus, to prevent premature transformation into liver stages, Plasmodium sporozoites exploit the same mechanism that regulates stress responses in mammalian cells.

ORGANISM(S): Plasmodium berghei Plasmodium falciparum

PROVIDER: GSE16259 | GEO | 2009/07/01

SECONDARY ACCESSION(S): PRJNA115095

REPOSITORIES: GEO

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Plasmodium berghei PbeIK2KO sporozoites

Project description:Malaria sporozoites, the form transmitted by mosquitoes, are quiescent while in the insect salivary glands. It is only after the sporozoites are deposited in the hostâs skin, migrate to the liver and infect hepatocytes that the parasites continue the life cycle. We show that the sporozoite latency is an active process that requires phosphorylation of the eukaryotic initiation factor-2Î± (eIF2Î±) by a sporozoite-specific kinase. Inactivation of the kinase gene leads to an overall enhancement of protein synthesis including of silenced liver stage proteins, and inhibits transmission of malaria. Specific inhibition of the eIF2Î± phosphatase by salubrinal has the opposite effect. Thus, to prevent premature transformation into liver stages, Plasmodium sporozoites exploit the same mechanism that regulates stress responses in mammalian cells. 4 samples overall, 2 wt and 2 KO (PbeIK2 knockout) samples

2010-05-16 | E-GEOD-16259 | biostudies-arrayexpress

CXCR4 is a host factor that regulates Plasmodium development in hepatocytes

Project description:The liver stage of the etiological agent of malaria, Plasmodium, is obligatory for successful infection of its various mammalian hosts. Differentiation of the rod-shaped sporozoites of Plasmodium into spherical exoerythrocytic forms (EEFs) via bulbous expansion is essential for parasite development in the liver. However, little is known about the host factors regulating the morphological transformation of Plasmodium sporozoites in this organ. Here, we show that sporozoite differentiation into EEFs in the liver involves protein kinase Cζ-mediated NF-κB activation, which robustly induces the expression of C-X-C chemokine receptor type 4 (CXCR4) in hepatocytes and subsequently elevates intracellular Ca2+ levels, thereby triggering sporozoite transformation into EEFs. Blocking CXCR4 expression by genetic or pharmacological intervention profoundly inhibited the liver stage development of the P. berghei rodent malaria parasite and the human P. falciparum parasite also. Collectively, our experiments show that CXCR4 is a key host factor for Plasmodium development in the liver, and CXCR4 warrants further investigation for malaria prophylaxis.

2019-05-29 | GSE130442 | GEO

Transcription profiling of mouse hepatocytes reinfected with Plasmodium berghei

Project description:We show that an ongoing malaria blood stage infection impairs the establishment of Plasmodium sporozoites in hepatocytes and that secondary infections can only be established after a previous infection has been cleared from circulation. Using control mice, mice infected with sporozoites only, mice infected by iRBCs only or mice reinfected, we show that this impairment is not due to an effect of the acquired host immune response or to a decrease in host cell survival. Instead, an ongoing blood stage infection leads to a significant increase in the expression of hepcidin, a peptide hormone that is secreted by the liver and controls body iron homeostasis. A rapid increase of hepcidin levels during blood stage infection causes sequestration of iron in storage forms within cells of reticuloendothelial system decreasing its availability in hepatocytes, where it is required for Plasmodium sporozoite establishment.

2010-11-01 | E-TABM-839 | biostudies-arrayexpress

Transcription profiling by array of Plasmodium berghei wild type and puf2 knock out in a time series

Project description:Many eukaryotic developmental and cell fate decisions are effected post-transcriptionally that mechanistically involve RNA binding proteins as regulators of translation of key mRNAs. In the unicellular eukaryote malaria parasite, Plasmodium, one of the most dramatic changes in cell morphology and function occurs during transmission between mosquito and human host. In the mosquito salivary glands, Plasmodium sporozoites are slender, motile and remain infectious for several weeks; only after transmission and liver cell invasion, does the parasite rapidly transform into a round, non-motile exo-erythrocytic form (EEF) that gives rise to thousands of infectious merozoites to be released into the blood stream. Here we demonstrate a Plasmodium homolog of the RNA binding protein, Pumilio, as a key regulator of the sporozoite to EEF transformation. In the absence of Pumilio-2 (Puf2) Plasmodium berghei sporozoites initiate early stage EEF development inside mosquito salivary glands with characteristic morphological changes; puf2- salivary gland sporozoites lose gliding motility, cell traversal ability and are less infective. Global expression profiling confirmed that transgenic parasites exhibit genome-wide transcriptional adaptations typical for Plasmodium intra-hepatic development. The data demonstrate that Puf2 is a key player in regulating developmental control, and imply that transformation of salivary gland-resident sporozoites into early liver stage parasites is regulated by a post-translational mechanism.

2010-11-01 | E-TABM-1067 | biostudies-arrayexpress

In-depth proteomic analysis of Plasmodium berghei sporozoites using trapped ion mobility spectrometry with parallel accumulation-serial fragmentation

Project description:We took advantage of a novel highly sensitive timsTOF PRO mass spectrometer, based on trapped ion mobility spectrometry with parallel accumulation-serial fragmentation. Combined with three alternative methods for sporozoite purification, this approach allowed us to identify the deep proteome of P. berghei sporozoites using low numbers of parasites. This study provides a reference proteome for P. berghei sporozoites, identifying a core set of proteins expressed accross species, and illustrates how the unprecedented sensitivity of the timsTOF PRO system enables deep proteomic analysis from limited sample amounts.

2021-02-11 | PXD022735 | Pride

Unraveling the Plasmodium vivax sporozoite transcriptional journey from mosquito vector to human host

Project description:Malaria parasites transmitted by mosquito bite are remarkably efficient in establishing human infections. The infection process requires ~30 minutes and is highly complex as quiescent sporozoites injected with mosquito saliva must be rapidly activated in the skin, migrate through the body, and infect the liver. This process is poorly understood for Plasmodium vivax due to low infectivity in the in vitro models. To study this skin-to-liver stage of malaria, we developed quantitative bioassays coupled with transcriptomics to evaluate parasite changes linked with mammalian microenvironmental factors. Our in vitro phenotype and RNA-seq analyses revealedkey microenvironmental relationships with distinct biological functions. M ost notable, preservation of sporozoite quiescence by exposure to insect-like factors coupled with strategic activation limits untimely activation of invasion-associated genes to dramatically increase hepatocyte invasion rates. We also report the first transcriptomic analysis of the P. vivax sporozoite interaction in salivary glands identifying 118 infection-related differentially-regulated Anopheles dirus genes. These results provide important new insights in malaria parasite biology and identify priority targets for antimalarial therapeutic interventions to block P. vivax infection.

2018-08-16 | GSE117538 | GEO

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

Project description:MalariaM-bM-^@M-^Ys 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 M-bM-^@M-^Xjust-in-timeM-bM-^@M-^Y 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. Wild-type (Py17XNL) and pypuf2 -salivary gland sporozoites

2012-10-27 | E-GEOD-41873 | biostudies-arrayexpress

Liver-resident memory CD8+ T cells form a front-line defense against malaria liver-stage infection.

Project description:In recent years, various intervention strategies have reduced malaria morbidity and mortality, but further improvements likely depend upon development of a broadly protective vaccine. To better understand immune requirement for protection, we examined liver-stage immunity after vaccination with irradiated sporozoites, an effective though logistically difficult vaccine. We identified a population of memory CD8+ T cells that expressed the gene signature of tissue-resident memory (Trm) T cells and remained permanently within the liver, where they patrolled the sinusoids. Exploring the requirements for liver Trm cell induction, we showed that by combining dendritic cell-targeted priming with liver inflammation and antigen recognition on hepatocytes, high frequencies of Trm cells could be induced and these cells were essential for protection against malaria sporozoite challenge. Our study highlights the immune potential of liver Trm cells and provides approaches for their selective transfer, expansion or depletion, which may be harnessed to control liver infections or autoimmunity.

2016-10-02 | GSE71518 | GEO

An in vitro model of intestinal infection reveals a developmentally regulated transcriptome of Toxoplasma sporozoites and a NF-κB-like signature in infected host cells

Project description:Toxoplasmosis is a zoonotic infection affecting approximately 30% of the world’s human population. After sexual reproduction in the definitive feline host, Toxoplasma oocysts, each containing 8 sporozoites, are shed into the environment where they can go on to infect humans and other warm-blooded intermediate hosts. Here, we use an in vitro model to assess host transcriptomic changes that occur in the earliest stages of such infections. We show that infection of rat intestinal epithelial cells with mature sporozoites primarily results in higher expression of genes associated with Tumor Necrosis Factor alpha (TNFα) signaling via NF-κB. Furthermore, we find that, consistent with their biology, these mature, invaded sporozoites display a transcriptome intermediate between the previously reported day 10 oocysts and that of their tachyzoite counterparts. Thus, this study uncovers novel host and pathogen factors that may be critical for the establishment of a successful intracellular niche following sporozoite-initiated infection.

2017-04-01 | GSE94473 | GEO

Single-cell sequencing of Plasmodium berghei sporozoites

Project description:Single‐cell RNA sequencing reveals developmental heterogeneity among P. berghei sporozoites Gene expression profiles of P. berghei midgut and salivary gland sporozoites at single-cell resolution

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