In Vivo Transcriptome of<i>Plasmodium falciparum</i>Reveals Overexpression of Transcripts That Encode Surface Proteins

Daily, Johanna P.; Roch, Karine G. Le; Sarr, Ousmane; Ndiaye, Daouda; Lukens, Amanda K.; Zhou, Yingyao; Ndir, O.; Mboup, S.; Sultan, Ali A.; Winzeler, Elizabeth A.; Wirth, Dyann F.

doi:10.1086/428289

Cited by 94 publications

(64 citation statements)

References 38 publications

(42 reference statements)

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“…PF14_0752 is part of the PHISTa subfamily, whose members are specific to P. falciparum (37). PF14_0752 was one of the most highly up-regulated genes in CD36-selected parasites (47), in field isolates (48), and in 3D7 gametocytes (49). Recently a PHISTc family member was shown to bind to the intracellular domain of PfEMP1 (50); however the function of other PHIST family members is unknown and awaits further research.…”

Section: Discussionmentioning

confidence: 99%

A subset of group A-like var genes encodes the malaria parasite ligands for binding to human brain endothelial cells

Claessens

Adams

Ghumra

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

198

230

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Cerebral malaria is the most deadly manifestation of infection with Plasmodium falciparum. The pathology of cerebral malaria is characterized by the accumulation of infected erythrocytes (IEs) in the microvasculature of the brain caused by parasite adhesins on the surface of IEs binding to human receptors on microvascular endothelial cells. The parasite and host molecules involved in this interaction are unknown. We selected three P. falciparum strains (HB3, 3D7, and IT/FCR3) for binding to a human brain endothelial cell line (HBEC-5i). The whole transcriptome of isogenic pairs of selected and unselected parasites was analyzed using a variant surface antigen-supplemented microarray chip. After selection, the most highly and consistently up-regulated genes were a subset of group A-like var genes (HB3var3, 3D7_PFD0020c, ITvar7, and ITvar19) that showed 11-to >100-fold increased transcription levels. These var genes encode P. falciparum erythrocyte membrane protein (PfEMP)1 variants with distinct N-terminal domain types (domain cassette 8 or domain cassette 13). Antibodies to HB3var3 and PFD0020c recognized the surface of live IEs and blocked binding to HBEC-5i, thereby confirming the adhesive function of these variants. The clinical in vivo relevance of the HBEC-selected parasites was supported by significantly higher surface recognition of HBEC-selected parasites compared with unselected parasites by antibodies from young African children suffering cerebral malaria (Mann-Whitney test, P = 0.029) but not by antibodies from controls with uncomplicated malaria (Mann-Whitney test, P = 0.58). This work describes a binding phenotype for virulence-associated group A P. falciparum erythrocyte membrane protein 1 variants and identifies targets for interventions to treat or prevent cerebral malaria.adherence | pathogenesis | sequestration

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Section: Discussionmentioning

confidence: 99%

A subset of group A-like var genes encodes the malaria parasite ligands for binding to human brain endothelial cells

Claessens

Adams

Ghumra

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

198

230

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“…Little variations were observed throughout the parasite erythrocytic stages with a general low coverage in FAIRE-seq and MAINE-seq (data not shown). These results are not surprising, considering that most of these genes seem to be heavily down regulated in vitro (Le Roch et al 2003;Daily et al 2005). Further investigation of the chromatin status in vivo will be required to understand the transcriptional regulation of these particular gene families.…”

Section: Chromatin Status and Parasite Virulencementioning

confidence: 93%

Nucleosome landscape and control of transcription in the human malaria parasite

Ponts¹,

Harris²,

Prudhomme³

et al. 2010

Genome Res.

129

179

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In eukaryotic cells, chromatin reorganizes within promoters of active genes to allow the transcription machinery and various transcription factors to access DNA. In this model, promoter-specific transcription factors bind DNA to initiate the production of mRNA in a tightly regulated manner. In the case of the human malaria parasite, Plasmodium falciparum, specific transcription factors are apparently underrepresented with regards to the size of the genome, and mechanisms underlying transcriptional regulation are controversial. Here, we investigate the modulation of DNA accessibility by chromatin remodeling during the parasite infection cycle. We have generated genome-wide maps of nucleosome occupancy across the parasite erythrocytic cycle using two complementary assays-the formaldehyde-assisted isolation of regulatory elements to extract protein-free DNA (FAIRE) and the MNase-mediated purification of mononucleosomes to extract histonebound DNA (MAINE), both techniques being coupled to high-throughput sequencing. We show that chromatin architecture undergoes drastic upheavals throughout the parasite's cycle, contrasting with targeted chromatin reorganization usually observed in eukaryotes. Chromatin loosens after the invasion of the red blood cell and then repacks prior to the next cycle. Changes in nucleosome occupancy within promoter regions follow this genome-wide pattern, with a few exceptions such as the var genes involved in virulence and genes expressed at early stages of the cycle. We postulate that chromatin structure and nucleosome turnover control massive transcription during the erythrocytic cycle. Our results demonstrate that the processes driving gene expression in Plasmodium challenge the classical eukaryotic model of transcriptional regulation occurring mostly at the transcription initiation level.

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“…One way to approach the analysis of parasite-specific factors in disease severity is to compare the transcriptional profiles of parasites taken directly from patients with different clinical presentations. Several such analyses have already been carried out but with conflicting conclusions (1)(2)(3)(4).…”

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confidence: 99%

Statistical estimation of cell-cycle progression and lineage commitment in Plasmodium falciparum reveals a homogeneous pattern of transcription in ex vivo culture

Lemieux

Gomez-Escobar

Feller

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

135

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We have cultured Plasmodium falciparum directly from the blood of infected individuals to examine patterns of mature-stage gene expression in patient isolates. Analysis of the transcriptome of P. falciparum is complicated by the highly periodic nature of gene expression because small variations in the stage of parasite development between samples can lead to an apparent difference in gene expression values. To address this issue, we have developed statistical likelihood-based methods to estimate cell cycle progression and commitment to asexual or sexual development lineages in our samples based on microscopy and gene expression patterns. In cases subsequently matched for temporal development, we find that transcriptional patterns in ex vivo culture display little variation across patients with diverse clinical profiles and closely resemble transcriptional profiles that occur in vitro. These statistical methods, available to the research community, assist in the design and interpretation of P. falciparum expression profiling experiments where it is difficult to separate true differential expression from cell-cycle dependent expression. We reanalyze an existing dataset of in vivo patient expression profiles and conclude that previously observed discrete variation is consistent with the commitment of a varying proportion of the parasite population to the sexual development lineage. malaria ͉ microarray

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In Vivo Transcriptome ofPlasmodium falciparumReveals Overexpression of Transcripts That Encode Surface Proteins

Cited by 94 publications

References 38 publications

A subset of group A-like var genes encodes the malaria parasite ligands for binding to human brain endothelial cells

A subset of group A-like var genes encodes the malaria parasite ligands for binding to human brain endothelial cells

Nucleosome landscape and control of transcription in the human malaria parasite

Statistical estimation of cell-cycle progression and lineage commitment in Plasmodium falciparum reveals a homogeneous pattern of transcription in ex vivo culture

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