Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

CXCR4 is a host factor that regulates Plasmodium development in hepatocytes

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE130442 | GEO | 2019/05/29

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

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

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

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 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.

2009-07-01 | GSE16259 | 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

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

Transcriptomic analysis of Plasmodium PBANKA, PBSLTRiP-KO, PB268-KO parasite infected and uninfected host cell

Project description:Liver stage of malaria parasite exports SLTRiP and PB268 to the cytosol of parasite infected host cell. To know the host genes perturbed by WT-PBANKA, SLTRiP-KO and PB268-KO parasite growth, we did transcriptomic sequencing of infected host cells. We did mRNA sequencing of four samples for comparative analysis of WT and PB-knockout parasites infected host cells at 22 hours of post sporozoites infection. mRNA profiles of Plasmodium PBANKA, PBSLTRiP-KO, PB268-KO parasite infected and uninfected HepG2 cells after 22hrs of sporozoites infections were generated by deep sequencing using Illumina GAIIx.

2016-07-03 | E-GEOD-53292 | biostudies-arrayexpress

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

Project description: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.

2012-10-27 | GSE41873 | GEO

Host cell transcripts during malaria liver stage infection reveals a coordinated and sequential set of biological events

Project description:After entering their mammalian host via the bite of an Anopheles mosquito, Plasmodium sporozoites migrate to the liver where they traverse several hepatocytes before invading the one inside which they will develop and multiply into thousands of merozoites. Although this constitutes an essential step in malaria infection, the requirements of Plasmodium parasites in liver cells and how they use the host cell for their own survival and development are poorly understood. To gain new insights into the molecular host-parasite interactions that take place during malaria liver infection, we have used high-throughput microarray technology to determine the transcriptional profile of P. yoelii-infected hepatocytes that were collected from P. yoelii-infected mice 24 and 40 h after infection. This in vivo microarray expression was compared with the microarray analysis of in vitro infected hepatoma cells infected with closely related rodent malaria parasite P. berghei. Differential expression patterns for host genes identify genes and pathways involved in the host response to rodent Plasmodium parasites. Keywords: gene expression

2010-02-24 | GSE14967 | GEO

Comparison of gene expression between wild type and AP2-G KO parasites.

Project description:In the rodent malaria parasite Plasmodium berghei, we found that an AP2 family transcription factor designated AP2-L plays a critical role in the development of the liver stage. Using DNA microarray analysis we showed that the expression of several genes, including those of parasitophorous vacuole membrane proteins, was significantly decreased in the early liver stage of AP2-L-depleted parasites. Gene expression of P. berghei sporozoites was compared between wild type and AP2-G KO parasites. Five biologically independent experiments were performed for each genotype.

2012-04-30 | E-GEOD-34806 | biostudies-arrayexpress

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

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data