Identification of a subtelomeric gene family expressed during the asexual–sexual stage transition in Plasmodium falciparum

Ekşi, Saliha; Haile, Yoseph; Furuya, Tetsuya; Ma, Liang; Su, Xin‐zhuan; Williamson, Kim C.

doi:10.1016/j.molbiopara.2005.05.010

Cited by 91 publications

(144 citation 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.

201

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.

201

230

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“…6C,D). Possible coordinated repression along a large chromosome region was only observed in a subtelomeric region of chromosome 14, which includes several genes involved in gametocyte formation (Eksi et al 2005), but further along the chromosome neighboring genes showed opposite expression patterns in some parasite lines (Fig. 6E).…”

Section: Epigenetic Variation In Malaria Parasitesmentioning

confidence: 98%

Transcriptional variation in the malaria parasitePlasmodium falciparum

Rovira-Graells¹,

Gupta²,

Planet³

et al. 2012

Genome Res.

207

342

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Malaria genetic variation has been extensively characterized, but the level of epigenetic plasticity remains largely unexplored. Here we provide a comprehensive characterization of transcriptional variation in the most lethal malaria parasite, Plasmodium falciparum, based on highly accurate transcriptional analysis of isogenic parasite lines grown under homogeneous conditions. This analysis revealed extensive transcriptional heterogeneity within genetically homogeneous clonal parasite populations. We show that clonally variant expression controlled at the epigenetic level is an intrinsic property of specific genes and gene families, the majority of which participate in host-parasite interactions. Intrinsic transcriptional variability is not restricted to genes involved in immune evasion, but also affects genes linked to lipid metabolism, protein folding, erythrocyte remodeling, or transcriptional regulation, among others, indicating that epigenetic variation results in both antigenic and functional variation. We observed a general association between heterochromatin marks and clonally variant expression, extending previous observations for specific genes to essentially all variantly expressed gene families. These results suggest that phenotypic variation of functionally unrelated P. falciparum gene families is mediated by a common mechanism based on reversible formation of H3K9me3-based heterochromatin. In changing environments, diversity confers fitness to a population. Our results support the idea that P. falciparum uses a bethedging strategy, as an alternative to directed transcriptional responses, to adapt to common fluctuations in its environment. Consistent with this idea, we found that transcriptionally different isogenic parasite lines markedly differed in their survival to heat-shock mimicking febrile episodes and adapted to periodic heat-shock with a pattern consistent with natural selection of pre-existing parasites.

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“…The constitutively expressed PF13_0272 gene was used as a control using primers C341F and C341R (supplementary material Table S1). For real-time RT-PCR analysis of genes expressed during early stages of gametocytogenesis, primers (supplementary material Table S1) were designed for Pfs16 (Moelans et al, 1991), Pfs27 (Alano et al, 1991), PfPeg3 (Lanfrancotti et al, 2007) and PF14_744 (Eksi et al, 2005). For sex-specific gene expression, primers were designed for the malespecific a-tubulin II gene and female-specific gene Pfs47 (Rawlings et al, 1992;van Schaijk et al, 2006).…”

Section: Rt-pcrmentioning

confidence: 99%

“…As developmental decision for gametocytogenesis occurs during the formation of the asexual schizont (Bruce et al, 1990), it is important that regulatory genes are expressed in schizonts that are committed to sexual differentiation (Alano, 2007). Global analyses of gene expression by several groups have revealed relatively small numbers of genes showing evidence of upregulation after induction of sexual development (Eksi et al, 2005;Silvestrini et al, 2005;Young et al, 2005). Some early gametocyte genes are probably involved in host cell remodeling, since they are found to be exported to the parasitophorous vacuole and/or the cytoplasm of erythrocytes (Eksi et al, 2005;Lanfrancotti et al, 2007).…”

mentioning

confidence: 99%

“…Global analyses of gene expression by several groups have revealed relatively small numbers of genes showing evidence of upregulation after induction of sexual development (Eksi et al, 2005;Silvestrini et al, 2005;Young et al, 2005). Some early gametocyte genes are probably involved in host cell remodeling, since they are found to be exported to the parasitophorous vacuole and/or the cytoplasm of erythrocytes (Eksi et al, 2005;Lanfrancotti et al, 2007). Others such as pfs27 and pfgig may play regulatory roles during the commitment to sexual development.…”

mentioning

confidence: 99%

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The Puf-family RNA-binding protein PfPuf2 regulates sexual development and sex differentiation in the malaria parasitePlasmodium falciparum

Miao

Fan

et al. 2010

Journal of Cell Science

110

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SummaryTranslation regulation plays an important role during gametocytogenesis in the malaria parasite, a process that is obligatory for the transmission of the parasite through mosquito vectors. In this study we determined the function of PfPuf2, a member of the Puf family of translational repressors, in gametocytogenesis of Plasmodium falciparum. Tagging of the endogenous PfPuf2 protein with green fluorescent protein showed that PfPuf2 was expressed in both male and female gametocytes, and the protein was localized in the cytoplasm of the parasite. Targeted disruption of the PfPuf2 gene did not affect asexual growth of the parasite, but promoted the formation of gametocytes and differentiation of male gametocytes. Complementation studies were performed to confirm that the resultant phenotypic changes were due to disruption of the PfPuf2 gene. Episomal expression of PfPuf2 under its cognate promoter almost restored the gametocytogenesis rate in a PfPuf2 disruptant to the level of the wild-type parasite. It also partially restored the effect of PfPuf2 disruption on male-female sex ratio. In addition, episomal overexpression of PfPuf2 under its cognate promoter but with a higher concentration of the selection drug or under the constitutive hsp86 promoter in both the PfPuf2-disruptant and wild-type 3D7 lines, further dramatically reduced gametocytogenesis rates and sex ratios. These findings suggest that in this early branch of eukaryotes the function of PfPuf2 is consistent with the ancestral function of suppressing differentiation proposed for Puf-family proteins. one Pumilio protein, it plays multiple roles in embryonic morphogenesis (Murata and Wharton, 1995), germline development and maintenance (Asaoka-Taguchi et al., 1999;Forbes and Lehmann, 1998;Parisi and Lin, 1999), and dendrite morphogenesis, neuronal excitability and learning (Mee et al., 2004;Menon et al., 2004;Muraro et al., 2008;Schweers et al., 2002;Ye et al., 2004). Based on related functions of Pufs in controlling germline switch in C. elegans, regulating aging and mitochondrial function in yeast, and promoting vegetative growth in the slime mold Dictyostelium (Souza et al., 1999), it has been suggested that the ancestral function of Puf proteins is to promote proliferation and to suppress differentiation .Translational regulation of gene expression in protozoan parasites is not well understood. In malaria parasites of the genus Plasmodium, the life cycle takes place in two hosts. In the blood of a vertebrate host, in response to poorly defined cues, a small proportion of the parasites differentiates into gametocytes, a process termed gametocytogenesis. Transmission to the mosquito vector is accomplished by the sexually dimorphic male and female gametocytes. Molecular investigations into the sexual biology of malaria parasites have led to the identification of a number of gametocyte-and sex-specific molecules and elucidation of their functions during sexual development (reviewed by Alano, 2007;Dixon et al., 2008;Kooij and Matuschewski, 2007;Talm...

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Identification of a subtelomeric gene family expressed during the asexual–sexual stage transition in Plasmodium falciparum

Cited by 91 publications

References 35 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

Transcriptional variation in the malaria parasitePlasmodium falciparum

The Puf-family RNA-binding protein PfPuf2 regulates sexual development and sex differentiation in the malaria parasitePlasmodium falciparum

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