88 results on '"Dixon, Matthew W. A."'
Search Results
52. Red Blood Cells Polarize Green Laser Light Revealing Hemoglobin′s Enhanced Non-Fundamental Raman Modes
- Author
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Marzec, Katarzyna M., primary, Perez-Guaita, David, additional, de Veij, Marleen, additional, McNaughton, Don, additional, Baranska, Malgorzata, additional, Dixon, Matthew W. A., additional, Tilley, Leann, additional, and Wood, Bayden R., additional
- Published
- 2014
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53. A female gametocyte-specific ABC transporter plays a role in lipid metabolism in the malaria parasite
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Tran, Phuong N., primary, Brown, Simon H. J., additional, Mitchell, Todd W., additional, Matuschewski, Kai, additional, McMillan, Paul J., additional, Kirk, Kiaran, additional, Dixon, Matthew W. A., additional, and Maier, Alexander G., additional
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- 2014
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54. Detection and Quantification of Early-Stage Malaria Parasites in Laboratory Infected Erythrocytes by Attenuated Total Reflectance Infrared Spectroscopy and Multivariate Analysis
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Khoshmanesh, Aazam, primary, Dixon, Matthew W. A., additional, Kenny, Shannon, additional, Tilley, Leann, additional, McNaughton, Don, additional, and Wood, Bayden R., additional
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- 2014
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55. Diagnosing malaria infected cells at the single cell level using focal plane array Fourier transform infrared imaging spectroscopy
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Wood, Bayden R., primary, Bambery, Keith. R., additional, Dixon, Matthew W. A., additional, Tilley, Leann, additional, Nasse, Michael J., additional, Mattson, Eric, additional, and Hirschmugl, Carol J., additional
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- 2014
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56. Erythrocyte ß spectrin can be genetically targeted to protect mice from malaria
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Lelliott, Patrick M., Huang, Hong Ming, Dixon, Matthew W., Namvar, Arman, Blanch, Adam J., Rajagopal, Vijay, Tilley, Leann, Coban, Cevayir, McMorran, Brendan J., Foote, Simon J., and Burgio, Gaetan
- Abstract
The malaria parasite hijacks host erythrocytes to shield itself from the immune system and proliferate. Red blood cell abnormalities can provide protection from malaria by impeding parasite invasion and growth within the cell or by compromising the ability of parasites to avoid host clearance. Here, we describe 2 N-ethyl-N-nitrosourea–induced mouse lines, SptbMRI26194 and SptbMRI53426, containing single-point mutations in the erythrocyte membrane skeleton gene, ß spectrin (Sptb), which exhibit microcytosis but retain a relatively normal ratio of erythrocyte surface area to volume and are highly resistant to rodent malaria. We propose the major factor responsible for malaria protection is the specific clearance of mutant erythrocytes, although an enhanced clearance of uninfected mutant erythrocytes was also observed (ie, the bystander effect). Using an in vivo erythrocyte tracking assay, we established that this phenomenon occurs irrespective of host environment, precluding the involvement of nonerythrocytic cells in the resistance mechanism. Furthermore, we recapitulated this phenotype by disrupting the interaction between ankyrin-1 and ß spectrin in vivo using CRISPR/Cas9 genome editing technology, thereby genetically validating a potential antimalarial target. This study sheds new light on the role of ß spectrin during Plasmodium infection and highlights how changes in the erythrocyte cytoskeleton can substantially influence malaria susceptibility with minimal adverse consequences for the host.
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- 2017
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57. Tracking Glideosome-Associated Protein 50 Reveals the Development and Organization of the Inner Membrane Complex of Plasmodium flaciparum
- Author
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Yeoman, Jeffrey A, Hanssen, Eric, Maier, Alex, Klonis, Nectarios, Maco, Bohumil, Baum, Jake, Turnbull, Lynne, Whitchurch, Cynthia B, Dixon, Matthew W. A, Tilley, Leann, Yeoman, Jeffrey A, Hanssen, Eric, Maier, Alex, Klonis, Nectarios, Maco, Bohumil, Baum, Jake, Turnbull, Lynne, Whitchurch, Cynthia B, Dixon, Matthew W. A, and Tilley, Leann
- Abstract
The most deadly of the human malaria parasites, Plasmodium falciparum, has different stages specialized for invasion of hepatocytes, erythrocytes, and the mosquito gut wall. In each case, host cell invasion is powered by an actin-myosin motor complex that is linked to an inner membrane complex (IMC) via a membrane anchor called the glideosome-associated protein 50 (PfGAP50). We generated P. falciparum transfectants expressing green fluorescent protein (GFP) chimeras of PfGAP50 (PfGAP50-GFP). Using immunoprecipitation and fluorescence photobleaching, we show that C-terminally tagged PfGAP50-GFP can form a complex with endogenous copies of the linker protein PfGAP45 and the myosin A tail domain-interacting protein (MTIP). Full-length PfGAP50-GFP is located in the endoplasmic reticulum in early-stage parasites and then redistributes to apical caps during the formation of daughter merozoites. In the final stage of schizogony, the PfGAP50-GFP profile extends further around the merozoite surface. Three-dimensional (3D) structured illumination microscopy reveals the early-stage IMC as a doubly punctured flat ellipsoid that separates to form claw-shaped apposed structures. A GFP fusion of PfGAP50 lacking the C-terminal membrane anchor is misdirected to the parasitophorous vacuole. Replacement of the acid phosphatase homology domain of PfGAP50 with GFP appears to allow correct trafficking of the chimera but confers a growth disadvantage.
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- 2011
58. The Plasmodium falciparum -infected red blood cell
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Tilley, Leann, Dixon, Matthew W. A, Kirk, Kiaran, Tilley, Leann, Dixon, Matthew W. A, and Kirk, Kiaran
- Abstract
Plasmodium falciparum, the most virulent of the human malaria parasites, causes up to one million deaths per year. The parasite spends part of its lifecycle inside the red blood cells (RBCs) of its host. As it grows it ingests the RBC cytoplasm, digesting it in an acidic vacuole. Free haem released during haemoglobin digestion is detoxified by conversion to inert crystals of haemozoin. Malaria pathology is evident during the blood stage of the infection and is exacerbated by adhesion of infected RBCs to blood vessel walls, which prevents splenic clearance of the infected cells. Cytoadherence is mediated by surface-exposed virulence proteins that bind to endothelial cell receptors. These 'adhesins' are exported to the RBC surface via an exomembrane system that is established outside the parasite in the host cell cytoplasm. Antimalarial drugs that interfere with haem detoxification, or target other parasite-specific processes, have been effective in the treatment of malaria, but their use has been dogged by the development of resistance. Similarly, efforts to develop an effective blood vaccine are hindered by the variability of surface-exposed antigens.Cell factsPlasmodium falciparum invades RBCs and develops through the 'ring' and 'trophozoite' stages, then divides to form an average of ∼20 daughter cells in the 'schizont' stage.The intraerythrocytic P. falciparum parasite consumes up to 70% of the host cell haemoglobin in an acidic digestive vacuole, generating a crystalline by-product called haemozoin.Plasmodium- infected RBCs rely almost entirely on glycolysis for energy.The parasite establishes an exomembrane system in the host RBC cytoplasm and this provides a pathway for trafficking proteins, including virulence determinants, to the RBC surface.Adhesion of P. falciparum-infected RBCs to blood vessel walls helps avoid splenic clearance and contributes to the clinical symptoms of the disease, including fatal complications.Quinoline antimalarials inhibit haemozoin
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- 2011
59. ThePlasmodiumtranslocon of exported proteins (PTEX) component thioredoxin-2 is important for maintaining normal blood-stage growth
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Matthews, Kathryn, primary, Kalanon, Ming, additional, Chisholm, Scott A., additional, Sturm, Angelika, additional, Goodman, Christopher D., additional, Dixon, Matthew W. A., additional, Sanders, Paul R., additional, Nebl, Thomas, additional, Fraser, Fiona, additional, Haase, Silvia, additional, McFadden, Geoffrey I., additional, Gilson, Paul R., additional, Crabb, Brendan S., additional, and de Koning-Ward, Tania F., additional
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- 2013
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60. Spatial and temporal mapping of the PfEMP1 export pathway inPlasmodium falciparum
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McMillan, Paul J., primary, Millet, Coralie, additional, Batinovic, Steven, additional, Maiorca, Mauro, additional, Hanssen, Eric, additional, Kenny, Shannon, additional, Muhle, Rebecca A., additional, Melcher, Martin, additional, Fidock, David A., additional, Smith, Joseph D., additional, Dixon, Matthew W. A., additional, and Tilley, Leann, additional
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- 2013
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61. Origin, composition, organization and function of the inner membrane complex of Plasmodium falciparum gametocytes
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Dearnley, Megan K., primary, Yeoman, Jeffrey A., additional, Hanssen, Eric, additional, Kenny, Shannon, additional, Turnbull, Lynne, additional, Whitchurch, Cynthia B., additional, Tilley, Leann, additional, and Dixon, Matthew W. A., additional
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- 2012
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62. Tracking Glideosome-Associated Protein 50 Reveals the Development and Organization of the Inner Membrane Complex of Plasmodium falciparum
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Yeoman, Jeffrey A., primary, Hanssen, Eric, additional, Maier, Alexander G., additional, Klonis, Nectarios, additional, Maco, Bohumil, additional, Baum, Jake, additional, Turnbull, Lynne, additional, Whitchurch, Cynthia B., additional, Dixon, Matthew W. A., additional, and Tilley, Leann, additional
- Published
- 2011
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63. Effect of Antimalarial Drugs onPlasmodium falciparumGametocytes
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Peatey, Christopher L., primary, Skinner‐Adams, Tina S., additional, Dixon, Matthew W. A., additional, McCarthy, James S., additional, Gardiner, Donald L., additional, and Trenholme, Katharine R., additional
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- 2009
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64. Selective permeabilization of the host cell membrane of Plasmodium falciparum-infected red blood cells with streptolysin O and equinatoxin II
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Jackson, Katherine E., primary, Spielmann, Tobias, additional, Hanssen, Eric, additional, Adisa, Akinola, additional, Separovic, Frances, additional, Dixon, Matthew W. A., additional, Trenholme, Katharine R., additional, Hawthorne, Paula L., additional, Gardiner, Don L., additional, Gilberger, Tim, additional, and Tilley, Leann, additional
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- 2007
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65. Organization and function of an actin cytoskeleton in P lasmodium falciparum gametocytes.
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Hliscs, Marion, Millet, Coralie, Dixon, Matthew W., Siden‐Kiamos, Inga, McMillan, Paul, and Tilley, Leann
- Subjects
PLASMODIUM falciparum ,MOSQUITO vectors ,ACTIN ,CYTOSKELETON ,GERM cells ,MICROBIAL virulence - Abstract
In preparation for transmission to its mosquito vector, P lasmodium falciparum, the most virulent of the human malaria parasites, adopts an unusual elongated shape. Here we describe a previously unrecognized actin-based cytoskeleton that is assembled in maturing P . falciparum gametocytes. Differential extraction reveals the presence of a highly stabilized population of F-actin at all stages of development. Super-resolution microscopy reveals an F-actin cytoskeleton that is concentrated at the ends of the elongating gametocyte but extends inward along the microtubule cytoskeleton. Formin-1 is also concentrated at the gametocyte ends suggesting a role in actin stabilization. Immunoelectron microscopy confirms that the actin cytoskeleton is located under the inner membrane complex rather than in the sub-alveolar space. In stage V gametocytes, the actin and microtubule cytoskeletons are reorganized in a coordinated fashion. The actin-depolymerizing agent, cytochalasin D, depletes actin from the end of the gametocytes, whereas the actin-stabilizing compound, jasplakinolide, induces formation of large bundles and prevents late-stage disassembly of the actin cytoskeleton. Long-term treatment with these compounds is associated with disruption of the normal mitochondrial organization and decreased gametocyte viability. [ABSTRACT FROM AUTHOR]
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- 2015
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66. CLAG�9 is located in the rhoptries of Plasmodium falciparum
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Gardiner, Donald L., primary, Spielmann, Tobias, additional, Dixon, Matthew W. A., additional, Hawthorne, Paula L., additional, Ortega, Maria R., additional, Anderson, Karen L., additional, Skinner-Adams, Tina S., additional, Kemp, David J., additional, and Trenholme, Katharine R., additional
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- 2004
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67. Mitochondrial metabolism of sexual and asexual blood stages of the malaria parasite Plasmodium falciparum.
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MacRae, James I., Dixon, Matthew W. A., Dearnley, Megan K., Chua, Hwa H., Chambers, Jennifer M., Kenny, Shannon, Bottova, Iveta, Tilley, Leann, and McConville, Malcolm J.
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PLASMODIUM falciparum , *MALARIA , *METABOLISM , *METABOLOMICS , *GERM cells , *MITOCHONDRIAL membranes , *AMINO acids - Abstract
Background: The carbon metabolism of the blood stages of Plasmodium falciparum, comprising rapidly dividing asexual stages and non-dividing gametocytes, is thought to be highly streamlined, with glycolysis providing most of the cellular ATP. However, these parasitic stages express all the enzymes needed for a canonical mitochondrial tricarboxylic acid (TCA) cycle, and it was recently proposed that they may catabolize glutamine via an atypical branched TCA cycle. Whether these stages catabolize glucose in the TCA cycle and what is the functional significance of mitochondrial metabolism remains unresolved. Results: We reassessed the central carbon metabolism of P. falciparum asexual and sexual blood stages, by metabolically labeling each stage with 13C-glucose and 13C-glutamine, and analyzing isotopic enrichment in key pathways using mass spectrometry. In contrast to previous findings, we found that carbon skeletons derived from both glucose and glutamine are catabolized in a canonical oxidative TCA cycle in both the asexual and sexual blood stages. Flux of glucose carbon skeletons into the TCA cycle is low in the asexual blood stages, with glutamine providing most of the carbon skeletons, but increases dramatically in the gametocyte stages. Increased glucose catabolism in the gametocyte TCA cycle was associated with increased glucose uptake, suggesting that the energy requirements of this stage are high. Significantly, whereas chemical inhibition of the TCA cycle had little effect on the growth or viability of asexual stages, inhibition of the gametocyte TCA cycle led to arrested development and death. Conclusions: Our metabolomics approach has allowed us to revise current models of P. falciparum carbon metabolism. In particular, we found that both asexual and sexual blood stages utilize a conventional TCA cycle to catabolize glucose and glutamine. Gametocyte differentiation is associated with a programmed remodeling of central carbon metabolism that may be required for parasite survival either before or after uptake by the mosquito vector. The increased sensitivity of gametocyte stages to TCA-cycle inhibitors provides a potential target for transmission-blocking drugs. [ABSTRACT FROM AUTHOR]
- Published
- 2013
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68. Spatial and temporal mapping of the PfEMP1 export pathway in Plasmodium falciparum.
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McMillan, Paul J., Millet, Coralie, Batinovic, Steven, Maiorca, Mauro, Hanssen, Eric, Kenny, Shannon, Muhle, Rebecca A., Melcher, Martin, Fidock, David A., Smith, Joseph D., Dixon, Matthew W. A., and Tilley, Leann
- Subjects
MICROBIAL virulence ,PLASMODIUM falciparum ,HISTIDINE ,VASCULAR endothelium ,ERYTHROCYTES - Abstract
The human malaria parasite, Plasmodium falciparum, modifies the red blood cells ( RBCs) that it infects by exporting proteins to the host cell. One key virulence protein, P. falciparum Erythrocyte Membrane Protein-1 ( PfEMP1), is trafficked to the surface of the infected RBC, where it mediates adhesion to the vascular endothelium. We have investigated the organization and development of the exomembrane system that is used for PfEMP1 trafficking. Maurer's cleft cisternae are formed early after invasion and proteins are delivered to these (initially mobile) structures in a temporally staggered and spatially segregated manner. Membrane- Associated Histidine- Rich Protein-2( MAHRP2)-containing tether-like structures are generated as early as 4 h post invasion and become attached to Maurer's clefts. The tether/ Maurer's cleft complex docks onto the RBC membrane at ∼ 20 h post invasion via a process that is not affected by cytochalasin D treatment. We have examined the trafficking of a GFP chimera of PfEMP1 expressed in transfected parasites. PfEMP1B- GFP accumulates near the parasite surface, within membranous structures exhibiting a defined ultrastructure, before being transferred to pre-formed mobile Maurer's clefts. Endogenous PfEMP1 and PfEMP1B- GFP are associated with Electron- Dense Vesicles that may be responsible for trafficking PfEMP1 from the Maurer's clefts to the RBC membrane. [ABSTRACT FROM AUTHOR]
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- 2013
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69. Temporal evaluation of commitment to sexual development in Plasmodium falciparum.
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Peatey, Christopher L., Dixon, Matthew W. A., Gardiner, Donald L., and Trenholme, Katharine R.
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PLASMODIUM falciparum , *MOSQUITOES , *GERM cells , *PLASMODIUM , *MALARIA , *POLYPEPTIDES , *CHOLERA toxin - Abstract
Background: The production of gametocytes is essential for transmission of malaria parasites from the mammalian host to the mosquito vector. However the process by which the asexual blood-stage parasite undergoes commitment to sexual development is not well understood. This process is known to be sensitive to environmental stimuli and it has been suggested that a G protein dependent system may mediate the switch, but there is little evidence that the Plasmodium falciparum genome encodes heterotrimeric G proteins. Previous studies have indicated that the malaria parasite can interact with endogenous erythrocyte G proteins, and other components of the cyclic nucleotide pathway have been identified in P. falciparum. Also, the polypeptide cholera toxin, which induces commitment to gametocytogenesis is known to catalyze the ADP-ribosylation of the αs class of heterotrimeric G protein α subunits in mammalian systems has been reported to detect a number of Gα subunits in P. falciparum-infected red cells. Methods: Cholera toxin and Mas 7 (a structural analogue of Mastoparan) were used to assess the role played by putative G protein signalling in the commitment process, both are reported to interact with different components of classical Gαs and Gαi/o signalling pathways. Their ability to induce gametocyte production in the transgenic P. falciparum line Pfs16-GFP was determined and downstream effects on the secondary messenger cAMP measured. Results: Treatment of parasite cultures with either cholera toxin or MAS 7 resulted in increased gametocyte production, but only treatment with MAS 7 resulted in a significant increase in cAMP levels. This indicates that MAS 7 acts either directly or indirectly on the P. falciparum adenylyl cyclase. Conclusion: The observation that cholera toxin treatment did not affect cAMP levels indicates that while addition of cholera toxin does increase gametocytogenesis the method by which it induces increased commitment is not immediately obvious, except that is unlikely to be via heterotrimeric G proteins [ABSTRACT FROM AUTHOR]
- Published
- 2013
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70. Role of Plasmodium falciparumProtein GEXP07 in Maurer’s Cleft Morphology, Knob Architecture, and P. falciparumEMP1 Trafficking
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McHugh, Emma, Carmo, Olivia M. S., Blanch, Adam, Looker, Oliver, Liu, Boyin, Tiash, Snigdha, Andrew, Dean, Batinovic, Steven, Low, Andy J. Y., Cho, Hyun-Jung, McMillan, Paul, Tilley, Leann, and Dixon, Matthew W. A.
- Abstract
The trafficking of the virulence antigen PfEMP1 and its presentation at the knob structures at the surface of parasite-infected RBCs are central to severe adhesion-related pathologies such as cerebral and placental malaria. This work adds to our understanding of how PfEMP1 is trafficked to the RBC membrane by defining the protein-protein interaction networks that function at the Maurer’s clefts controlling PfEMP1 loading and unloading. We characterize a protein needed for virulence protein trafficking and provide new insights into the mechanisms for host cell remodeling, parasite survival within the host, and virulence.
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- 2020
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71. Ankyrin-1 Gene Exhibits Allelic Heterogeneity in Conferring Protection Against Malaria.
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Hong Ming Huang, Bauer, Denis C., Lelliott, Patrick M., Dixon, Matthew W. A., Tilley, Leann, McMorran, Brendan J., Foote, Simon J., and Burgio, Gaetan
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MALARIA treatment , *ANKYRINS - Abstract
Allelic heterogeneity is a common phenomenon where a gene exhibits a different phenotype depending on the nature of its genetic mutations. In the context of genes affecting malaria susceptibility, it allowed us to explore and understand the intricate host-parasite interactions during malaria infections. In this study, we described a gene encoding erythrocytic ankyrin-1 (Ank-1) which exhibits allelic-dependent heterogeneous phenotypes during malaria infections. We conducted an ENU mutagenesis screen on mice and identified two Ank-1 mutations, one resulting in an amino acid substitution (MRI95845), and the other a truncated Ank-1 protein (MRI96570). Both mutations caused hereditary spherocytosis-like phenotypes and confer differing protection against Plasmodium chabaudi infections. Upon further examination, the Ank-1(MRI96570) mutation was found to inhibit intraerythrocytic parasite maturation, whereas Ank-1(MRI95845) caused increased bystander erythrocyte clearance during infection. This is the first description of allelic heterogeneity in ankyrin-1 from the direct comparison between two Ank-1 mutations. Despite the lack of direct evidence from population studies, this data further supported the protective roles of ankyrin-1 mutations in conferring malaria protection. This study also emphasized the importance of such phenomena in achieving a better understanding of host-parasite interactions, which could be the basis of future studies. [ABSTRACT FROM AUTHOR]
- Published
- 2017
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72. The M18 Aspartyl Aminopeptidase of the Human Malaria Parasite Plasmodium faIciparum.
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Teuscher, Franka, Lowther, Jonathan, Skinner-Adams, Tina S., Spielmann, Tobias, Dixon, Matthew W. A., Stack, Colin M., Donnelly, Sheila, Mucha, Artur, Kafarski, Pawet, Vassiliou, Stamatia, Gardiner, Donald L., Dalton, John P., and Trenholme, Katharine R.
- Subjects
- *
GENE expression , *PLASMODIUM falciparum , *AMINOPEPTIDASES , *HEMOGLOBIN polymorphisms , *HYDROGEN-ion concentration , *BLOOD proteins , *IMMUNOBLOTTING , *GENOTYPE-environment interaction - Abstract
A member of the M18 family of aspartyl aminopeptidases is expressed by all intra-erythrocytic stages of the human malaria parasite Plasmodium falciparum (PfM18AAP), with highest expression levels in rings. Functionally active recombinant enzyme, rPfM18AAP, and native enzyme in cytosolic extracts of malaria parasites are 560-kDa octomers that exhibit optimal activity at neutral pH and require the presence of metal ions to maintain enzymatic activity and stability. Like the human aspartyl aminopeptidase, the exopeptidase activity of PfM18AAP is exclusive to N-terminal acidic amino acids, glutamate and aspartate, making this enzyme of particular interest and suggesting that it may function alongside the malaria cytosolie neutral aminopeptidases in the release of amino acids from host hemoglobin-derived peptides. Whereas immunocytochemical studies using transgenic P. falciparum parasites show that PfM18AAP is expressed in the cytosol, immunoblotting experiments revealed that the enzyme is also trafficked out of the parasite into the surrounding parasitophorous vacuole. Antisensemediated knockdown of PfM18AAP results in a lethal phenotype as a result of significant intracellular damage and validates this enzyme as a target at which novel antimalarial drugs could be directed. Novel phosphinic derivatives of aspartate and glutamate showed modest inhibition of rPfMI8AAP but did not inhibit malaria growth in culture. However, we were able to draw valuable observations concerning the structureactivity relationship of these inhibitors that can be employed in future inhibitor optimization studies. [ABSTRACT FROM AUTHOR]
- Published
- 2007
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73. VAR2CSA Ectodomain Labeling in Plasmodium falciparum Infected Red Blood Cells and Analysis via Flow Cytometry.
- Author
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Carmo OMS and Dixon MWA
- Abstract
Presentation of the variant antigen Plasmodium falciparum erythrocyte membrane protein 1 (EMP1) at the surface of infected red blood cells (RBCs) underpins the malaria parasite's pathogenicity. The transport of EMP1 to the RBC surface is facilitated by a parasite-derived trafficking system, in which over 500 parasite proteins are exported into the host cell cytoplasm. To understand how genetic ablation of selected exported proteins affects EMP1 transport, several EMP1 surface presentation assays have been developed, including: 1) trypsinization of surface-exposed EMP1 and analysis by SDS-PAGE and immunoblotting; and 2) infected RBC binding assays, to determine binding efficiency to immobilized ligand under physiological flow conditions. Here, we describe a third EMP1 surface presentation assay, where antibodies to the ectodomain of EMP1 and flow cytometry are used to quantify surface-exposed EMP1 in live cells. The advantages of this assay include higher throughput capacity and data better suited for robust quantitative analysis. This protocol can also be applied to other cellular contexts where an antibody can be developed for the ectodomain of the protein of interest., Competing Interests: Competing interestsThe authors have declared that no competing interests exists., (©Copyright : © 2023 The Authors; This is an open access article under the CC BY license.)
- Published
- 2023
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74. Multimodal imaging reveals membrane skeleton reorganisation during reticulocyte maturation and differences in dimple and rim regions of mature erythrocytes.
- Author
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Blanch AJ, Nunez-Iglesias J, Namvar A, Menant S, Looker O, Rajagopal V, Tham WH, Tilley L, and Dixon MWA
- Abstract
The red blood cell (RBC) is remarkable in its ability to deform as it passages through the vasculature. Its deformability derives from a spectrin-actin protein network that supports the cell membrane and provides strength and flexibility, however questions remain regarding the assembly and maintenance of the skeletal network. Using scanning electron microscopy (SEM) and atomic force microscopy (AFM) we have examined the nanoscale architecture of the cytoplasmic side of membrane discs prepared from reticulocytes and mature RBCs. Immunofluorescence microscopy was used to probe the distribution of spectrin and other membrane skeleton proteins. We found that the cell surface area decreases by up to 30% and the spectrin-actin network increases in density by approximately 20% as the reticulocyte matures. By contrast, the inter-junctional distance and junctional density increase only by 3-4% and 5-9%, respectively. This suggests that the maturation-associated reduction in surface area is accompanied by an increase in spectrin self-association to form higher order oligomers. We also examined the mature RBC membrane in the edge (rim) and face (dimple) regions of mature RBCs and found the rim contains about 1.5% more junctional complexes compared to the dimple region. A 2% increase in band 4.1 density in the rim supports these structural measurements., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2021 The Author(s).)
- Published
- 2021
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75. Plasmodium falciparum goes bananas for sex.
- Author
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Dixon MWA and Tilley L
- Subjects
- Animals, Biomechanical Phenomena, Erythrocytes parasitology, Female, Hepatocytes parasitology, Host-Parasite Interactions genetics, Humans, Malaria, Falciparum transmission, Male, Microtubules parasitology, Microtubules ultrastructure, Plasmodium falciparum cytology, Plasmodium falciparum genetics, Plasmodium falciparum metabolism, Reproduction, Asexual, Culicidae parasitology, Gametogenesis, Insect Vectors parasitology, Life Cycle Stages genetics, Malaria, Falciparum parasitology, Plasmodium falciparum growth & development
- Abstract
The sexual blood stages of the human malaria parasite Plasmodium falciparum undergo a remarkable transformation from a roughly spherical shape to an elongated crescent or "falciform" morphology from which the species gets its name. In this review, the molecular events that drive this spectacular shape change are discussed and some questions that remain regarding the mechanistic underpinnings are posed. We speculate on the role of the shape changes in promoting sequestration and release of the developing gametocyte, thereby facilitating parasite survival in the host and underpinning transmission to the mosquito vector., (Copyright © 2021. Published by Elsevier B.V.)
- Published
- 2021
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76. Multimodal analysis of Plasmodium knowlesi-infected erythrocytes reveals large invaginations, swelling of the host cell, and rheological defects.
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Liu B, Blanch AJ, Namvar A, Carmo O, Tiash S, Andrew D, Hanssen E, Rajagopal V, Dixon MWA, and Tilley L
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- Cytoplasm metabolism, Cytoplasm ultrastructure, Erythrocyte Membrane ultrastructure, Erythrocytes cytology, Erythrocytes ultrastructure, Hemoglobins metabolism, Host-Parasite Interactions, Humans, Merozoites ultrastructure, Microscopy, Electron, Scanning, Osmotic Pressure, Plasmodium falciparum growth & development, Plasmodium falciparum pathogenicity, Plasmodium knowlesi growth & development, Plasmodium knowlesi pathogenicity, Schizonts ultrastructure, Trophozoites ultrastructure, Vacuoles metabolism, Vacuoles ultrastructure, Erythrocyte Membrane metabolism, Erythrocytes parasitology, Plasmodium knowlesi ultrastructure
- Abstract
The simian parasite Plasmodium knowlesi causes severe and fatal malaria infections in humans, but the process of host cell remodelling that underpins the pathology of this zoonotic parasite is only poorly understood. We have used serial block-face scanning electron microscopy to explore the topography of P. knowlesi-infected red blood cells (RBCs) at different stages of asexual development. The parasite elaborates large flattened cisternae (Sinton Mulligan's clefts) and tubular vesicles in the host cell cytoplasm, as well as parasitophorous vacuole membrane bulges and blebs, and caveolar structures at the RBC membrane. Large invaginations of host RBC cytoplasm are formed early in development, both from classical cytostomal structures and from larger stabilised pores. Although degradation of haemoglobin is observed in multiple disconnected digestive vacuoles, the persistence of large invaginations during development suggests inefficient consumption of the host cell cytoplasm. The parasite eventually occupies ~40% of the host RBC volume, inducing a 20% increase in volume of the host RBC and an 11% decrease in the surface area to volume ratio, which collectively decreases the ability of the P. knowlesi-infected RBCs to enter small capillaries of a human erythrocyte microchannel analyser. Ektacytometry reveals a markedly decreased deformability, whereas correlative light microscopy/scanning electron microscopy and python-based skeleton analysis (Skan) reveal modifications to the surface of infected RBCs that underpin these physical changes. We show that P. knowlesi-infected RBCs are refractory to treatment with sorbitol lysis but are hypersensitive to hypotonic lysis. The observed physical changes in the host RBCs may underpin the pathology observed in patients infected with P. knowlesi., (© 2019 The Authors. Cellular Microbiology Published by John Wiley & Sons Ltd.)
- Published
- 2019
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77. Ankyrin-1 Gene Exhibits Allelic Heterogeneity in Conferring Protection Against Malaria.
- Author
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Huang HM, Bauer DC, Lelliott PM, Dixon MWA, Tilley L, McMorran BJ, Foote SJ, and Burgio G
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- Animals, Disease Models, Animal, Disease Resistance genetics, Erythrocytes metabolism, Erythrocytes parasitology, Erythrocytes pathology, Erythrocytes ultrastructure, Female, Malaria blood, Malaria parasitology, Malaria pathology, Male, Mice, Mutation, Osmotic Fragility genetics, Phenotype, Spherocytosis, Hereditary genetics, Spherocytosis, Hereditary pathology, Whole Genome Sequencing, Alleles, Ankyrins genetics, Genetic Heterogeneity, Genetic Predisposition to Disease, Host-Parasite Interactions genetics, Malaria genetics
- Abstract
Allelic heterogeneity is a common phenomenon where a gene exhibits a different phenotype depending on the nature of its genetic mutations. In the context of genes affecting malaria susceptibility, it allowed us to explore and understand the intricate host-parasite interactions during malaria infections. In this study, we described a gene encoding erythrocytic ankyrin-1 ( Ank-1 ) which exhibits allelic-dependent heterogeneous phenotypes during malaria infections. We conducted an ENU mutagenesis screen on mice and identified two Ank-1 mutations, one resulting in an amino acid substitution (MRI95845), and the other a truncated Ank-1 protein (MRI96570). Both mutations caused hereditary spherocytosis-like phenotypes and confer differing protection against Plasmodium chabaudi infections. Upon further examination, the Ank-1
(MRI96570) mutation was found to inhibit intraerythrocytic parasite maturation, whereas Ank-1(MRI95845) caused increased bystander erythrocyte clearance during infection. This is the first description of allelic heterogeneity in ankyrin-1 from the direct comparison between two Ank-1 mutations. Despite the lack of direct evidence from population studies, this data further supported the protective roles of ankyrin-1 mutations in conferring malaria protection. This study also emphasized the importance of such phenomena in achieving a better understanding of host-parasite interactions, which could be the basis of future studies., (Copyright © 2017 Huang et al.)- Published
- 2017
- Full Text
- View/download PDF
78. A Plasmodium falciparum S33 proline aminopeptidase is associated with changes in erythrocyte deformability.
- Author
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da Silva FL, Dixon MW, Stack CM, Teuscher F, Taran E, Jones MK, Lovas E, Tilley L, Brown CL, Trenholme KR, Dalton JP, Gardiner DL, and Skinner-Adams TS
- Subjects
- Amino Acid Sequence, Aminopeptidases chemistry, Aminopeptidases genetics, Aminopeptidases immunology, Antibodies, Protozoan immunology, Blotting, Northern, Blotting, Western, Cell Adhesion physiology, Elasticity, Erythrocyte Membrane genetics, Erythrocyte Membrane physiology, Erythrocytes parasitology, Gene Knockout Techniques, Humans, Microscopy, Atomic Force, Microscopy, Electron, Transmission, Microscopy, Fluorescence, Plasmodium falciparum genetics, RNA, Protozoan chemistry, Real-Time Polymerase Chain Reaction, Recombinant Proteins chemistry, Recombinant Proteins genetics, Recombinant Proteins immunology, Recombinant Proteins metabolism, Sequence Alignment, Transfection, Aminopeptidases metabolism, Erythrocyte Deformability physiology, Plasmodium falciparum enzymology
- Abstract
Infection with the apicomplexan parasite Plasmodium falciparum is a major cause of morbidity and mortality worldwide. One of the striking features of this parasite is its ability to remodel and decrease the deformability of host red blood cells, a process that contributes to disease. To further understand the virulence of Pf we investigated the biochemistry and function of a putative Pf S33 proline aminopeptidase (PfPAP). Unlike other P. falciparum aminopeptidases, PfPAP contains a predicted protein export element that is non-syntenic with other human infecting Plasmodium species. Characterization of PfPAP demonstrated that it is exported into the host red blood cell and that it is a prolyl aminopeptidase with a preference for N-terminal proline substrates. In addition genetic deletion of this exopeptidase was shown to lead to an increase in the deformability of parasite-infected red cells and in reduced adherence to the endothelial cell receptor CD36 under flow conditions. Our studies suggest that PfPAP plays a role in the rigidification and adhesion of infected red blood cells to endothelial surface receptors, a role that may make this protein a novel target for anti-disease interventions strategies., (Copyright © 2016 Elsevier Inc. All rights reserved.)
- Published
- 2016
- Full Text
- View/download PDF
79. Plasmodium species: master renovators of their host cells.
- Author
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de Koning-Ward TF, Dixon MW, Tilley L, and Gilson PR
- Subjects
- Amino Acid Motifs, Animals, Erythrocytes physiology, Humans, Immune Evasion, Plasmodium berghei genetics, Plasmodium berghei pathogenicity, Plasmodium berghei physiology, Plasmodium falciparum genetics, Plasmodium falciparum pathogenicity, Protein Sorting Signals, Protein Translocation Systems metabolism, Protozoan Proteins chemistry, Protozoan Proteins genetics, Transport Vesicles, Erythrocytes parasitology, Host-Pathogen Interactions, Malaria parasitology, Malaria, Falciparum parasitology, Plasmodium falciparum physiology, Protein Transport, Protozoan Proteins metabolism
- Abstract
Plasmodium parasites, the causative agents of malaria, have developed elaborate strategies that they use to survive and thrive within different intracellular environments. During the blood stage of infection, the parasite is a master renovator of its erythrocyte host cell, and the changes in cell morphology and function that are induced by the parasite promote survival and contribute to the pathogenesis of severe malaria. In this Review, we discuss how Plasmodium parasites use the protein trafficking motif Plasmodium export element (PEXEL), protease-mediated polypeptide processing, a novel translocon termed the Plasmodium translocon of exported proteins (PTEX) and exomembranous structures to export hundreds of proteins to discrete subcellular locations in the host erythrocytes, which enables the parasite to gain access to vital nutrients and to evade the immune defence mechanisms of the host.
- Published
- 2016
- Full Text
- View/download PDF
80. Shape-shifting gametocytes: how and why does P. falciparum go banana-shaped?
- Author
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Dixon MW, Dearnley MK, Hanssen E, Gilberger T, and Tilley L
- Subjects
- Animals, Cell Membrane, Culicidae parasitology, Humans, Plasmodium falciparum cytology, Spleen parasitology, Life Cycle Stages physiology, Plasmodium falciparum growth & development
- Abstract
Plasmodium falciparum is named for the crescent or falciform shape it adopts when preparing to undergo transfer to a mosquito vector. By contrast, gametocytes of the other (less virulent) human malaria parasites retain a more rounded shape. We describe the machinery that elongates falciparum gametocytes and discuss its relation with the machinery that elongates the invasive zoites. We address the question - why do falciparum malaria gametocytes go banana-shaped? The answer may lie in the finding that gametocyte maturation is associated with an increase in cellular deformability. The shape-shifting ability of gametocytes may facilitate the sequestration of early-stage gametocytes, while enabling late-stage gametocytes to circulate in the blood stream without being removed by the mechanical filtering mechanisms in the host spleen., (Copyright © 2012 Elsevier Ltd. All rights reserved.)
- Published
- 2012
- Full Text
- View/download PDF
81. Soft X-ray microscopy analysis of cell volume and hemoglobin content in erythrocytes infected with asexual and sexual stages of Plasmodium falciparum.
- Author
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Hanssen E, Knoechel C, Dearnley M, Dixon MW, Le Gros M, Larabell C, and Tilley L
- Subjects
- Calibration, Cell Shape, Cell Size, Erythrocytes metabolism, Erythrocytes ultrastructure, Germ Cells physiology, Germ Cells ultrastructure, Humans, Microscopy, Microscopy, Electron, Transmission, Plasmodium falciparum ultrastructure, Reproduction, Asexual, Serum Albumin, Bovine chemistry, Single-Cell Analysis, Spores, Protozoan ultrastructure, Tomography, X-Ray, X-Ray Absorption Spectroscopy, Erythrocytes parasitology, Hemoglobins metabolism, Plasmodium falciparum physiology
- Abstract
Plasmodium falciparum, the most virulent agent of human malaria, undergoes both asexual cycling and sexual differentiation inside erythrocytes. As the intraerythrocytic parasite develops it increases in size and alters the permeability of the host cell plasma membrane. An intriguing question is: how is the integrity of the host erythrocyte maintained during the intraerythrocytic cycle? We have used water window cryo X-ray tomography to determine cell morphology and hemoglobin content at different stages of asexual and sexual differentiation. The cryo stabilization preserves native structure permitting accurate analyses of parasite and host cell volumes. Absorption of soft X-rays by protein adheres to Beer-Lambert's law permitting quantitation of the concentration of hemoglobin in the host cell compartment. During asexual development the volume of the parasite reaches about 50% of the uninfected erythrocyte volume but the infected erythrocyte volume remains relatively constant. The total hemoglobin content gradually decreases during the 48h cycle but its concentration remains constant until early trophozoite stage, decreases by 25%, then remains constant again until just prior to rupture. During early sexual development the gametocyte has a similar morphology to a trophozoite but then undergoes a dramatic shape change. Our cryo X-ray tomography analysis reveals that about 70% of the host cell hemoglobin is taken up and digested during gametocyte development and the parasite eventually occupies about 50% of the uninfected erythrocyte volume. The total volume of the infected erythrocyte remains constant, apart from some reversible shrinkage at stage IV, while the concentration of hemoglobin decreases to about 70% of that in an uninfected erythrocyte., (Copyright © 2011 Elsevier Inc. All rights reserved.)
- Published
- 2012
- Full Text
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82. The Plasmodium falciparum-infected red blood cell.
- Author
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Tilley L, Dixon MW, and Kirk K
- Subjects
- Animals, Antigenic Variation, Antigens, Protozoan immunology, Antigens, Protozoan metabolism, Cell Adhesion, Drug Resistance, Endothelium, Vascular metabolism, Erythrocytes parasitology, Erythrocytes pathology, Humans, Life Cycle Stages, Malaria, Falciparum pathology, Malaria, Falciparum physiopathology, Plasmodium falciparum growth & development, Plasmodium falciparum pathogenicity, Antimalarials therapeutic use, Erythrocytes metabolism, Malaria, Falciparum drug therapy, Malaria, Falciparum parasitology, Plasmodium falciparum physiology
- Abstract
Plasmodium falciparum, the most virulent of the human malaria parasites, causes up to one million deaths per year. The parasite spends part of its lifecycle inside the red blood cells (RBCs) of its host. As it grows it ingests the RBC cytoplasm, digesting it in an acidic vacuole. Free haem released during haemoglobin digestion is detoxified by conversion to inert crystals of haemozoin. Malaria pathology is evident during the blood stage of the infection and is exacerbated by adhesion of infected RBCs to blood vessel walls, which prevents splenic clearance of the infected cells. Cytoadherence is mediated by surface-exposed virulence proteins that bind to endothelial cell receptors. These 'adhesins' are exported to the RBC surface via an exomembrane system that is established outside the parasite in the host cell cytoplasm. Antimalarial drugs that interfere with haem detoxification, or target other parasite-specific processes, have been effective in the treatment of malaria, but their use has been dogged by the development of resistance. Similarly, efforts to develop an effective blood vaccine are hindered by the variability of surface-exposed antigens., (Copyright © 2011 Elsevier Ltd. All rights reserved.)
- Published
- 2011
- Full Text
- View/download PDF
83. A green fluorescent protein-based assay for determining gametocyte production in Plasmodium falciparum.
- Author
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Dixon MW, Peatey CL, Gardiner DL, and Trenholme KR
- Subjects
- Animals, Antigens, Protozoan genetics, Antigens, Protozoan metabolism, Cell Separation, Gametogenesis, Green Fluorescent Proteins metabolism, Membrane Proteins genetics, Membrane Proteins metabolism, Plasmodium falciparum metabolism, Protozoan Proteins genetics, Protozoan Proteins metabolism, Flow Cytometry, Green Fluorescent Proteins genetics, Plasmodium falciparum growth & development
- Abstract
Study of the formation of the sexual blood stages of the malaria parasite has been significantly hampered by the absence of a reliable, reproducible assay devoid of operator bias and error. Here we report on the development of an assay utilizing a green fluorescent protein chimera of the early sexual blood stage protein Pfs16 as a marker for commitment to gametocytogenesis. Analysis of parasites via fluorescence activated cell sorting allows for the accurate assessment of gametocyte production well before morphological changes are apparent.
- Published
- 2009
- Full Text
- View/download PDF
84. Sex in Plasmodium: a sign of commitment.
- Author
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Dixon MW, Thompson J, Gardiner DL, and Trenholme KR
- Subjects
- Animals, Female, Gene Expression Regulation, Developmental, Host-Parasite Interactions, Male, Sex Characteristics, Sporozoites growth & development, Sporozoites physiology, Life Cycle Stages, Plasmodium physiology, Protozoan Proteins physiology, Sex Differentiation genetics
- Abstract
The gametocyte, or sexual blood-stage, of the malaria parasite represents the only stage of the parasite that can be transmitted to the mosquito vector following sexual development within the infected bloodmeal. Little is known about the processes leading to this cellular differentiation and specialization. The recent completion of the Plasmodium genome, and subsequent transcriptome and proteome analyses have revealed for the first time a molecular map of the genes that are differentially regulated at the onset of and during gametocytogenesis. In this review, we outline the underlying mechanisms involved in this process, focusing on the transition between the asexual and the sexual blood-stages of the parasite.
- Published
- 2008
- Full Text
- View/download PDF
85. Reliable transfection of Plasmodium falciparum using non-commercial plasmid mini preparations.
- Author
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Spielmann T, Dixon MW, Hernandez-Valladares M, Hannemann M, Trenholme KR, and Gardiner DL
- Subjects
- Animals, DNA, Protozoan genetics, Genes, Protozoan genetics, Membrane Proteins genetics, Protozoan Proteins genetics, Transgenes genetics, Plasmids genetics, Plasmodium falciparum genetics, Transfection methods
- Abstract
Transfection of Plasmodium falciparum is instrumental in the research on this parasite. However, the actual transfection protocol has not changed significantly since the first description and it is generally believed that large amounts of highly pure plasmid DNA are needed for successful transfection. Here, we report the transfection of P. falciparum using a protocol based on non-commercial mini-preparations of plasmid DNA. This method permits the reliable transfection of P. falciparum using less resources and lower costs, with a success rate comparable with currently used methods. A moderate throughput may be achieved using this method, providing a first step towards systematic transfection approaches in this parasite.
- Published
- 2006
- Full Text
- View/download PDF
86. A cluster of ring stage-specific genes linked to a locus implicated in cytoadherence in Plasmodium falciparum codes for PEXEL-negative and PEXEL-positive proteins exported into the host cell.
- Author
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Spielmann T, Hawthorne PL, Dixon MW, Hannemann M, Klotz K, Kemp DJ, Klonis N, Tilley L, Trenholme KR, and Gardiner DL
- Subjects
- Animals, Chromosomes genetics, Cytoplasm metabolism, Erythrocytes cytology, Exons genetics, Genome, Protozoan genetics, Mice, Physical Chromosome Mapping, Plasmodium falciparum cytology, Plasmodium falciparum pathogenicity, Protein Transport, Recombinant Proteins metabolism, Sequence Homology, Amino Acid, Solubility, Virulence, Genes, Protozoan genetics, Life Cycle Stages, Plasmodium falciparum growth & development, Plasmodium falciparum metabolism, Protozoan Proteins metabolism
- Abstract
Blood stages of Plasmodium falciparum export proteins into their erythrocyte host, thereby inducing extensive host cell modifications that become apparent after the first half of the asexual development cycle (ring stage). This is responsible for a major part of parasite virulence. Export of many parasite proteins depends on a sequence motif termed Plasmodium export element (PEXEL) or vacuolar transport signal (VTS). This motif has allowed the prediction of the Plasmodium exportome. Using published genome sequence, we redetermined the boundaries of a previously studied region linked to P. falciparum virulence, reducing the number of candidate genes in this region to 13. Among these, we identified a cluster of four ring stage-specific genes, one of which is known to encode an exported protein. We demonstrate that all four genes code for proteins exported into the host cell, although only two genes contain an obvious PEXEL/VTS motif. We propose that the systematic analysis of ring stage-specific genes will reveal a cohort of exported proteins not present in the currently predicted exportome. Moreover, this provides further evidence that host cell remodeling is a major task of this developmental stage. Biochemical and photobleaching studies using these proteins reveal new properties of the parasite-induced membrane compartments in the host cell. This has important implications for the biogenesis and connectivity of these structures.
- Published
- 2006
- Full Text
- View/download PDF
87. Implication of a Plasmodium falciparum gene in the switch between asexual reproduction and gametocytogenesis.
- Author
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Gardiner DL, Dixon MW, Spielmann T, Skinner-Adams TS, Hawthorne PL, Ortega MR, Kemp DJ, and Trenholme KR
- Subjects
- Animals, Antigens, Protozoan biosynthesis, Antigens, Protozoan metabolism, Blotting, Northern, Gametogenesis genetics, Genetic Complementation Test, Membrane Proteins biosynthesis, Membrane Proteins metabolism, Plasmodium falciparum genetics, Reproduction, Asexual genetics, Genes, Protozoan, Plasmodium falciparum physiology
- Abstract
Gametocytogenesis is fundamental for transmission of the malaria parasite Plasmodium falciparum from the human host to the mosquito vector, yet very little is understood about what triggers the switch between asexual reproduction and gametocytogenesis. Arresting the progression through the sexual cycle would block transmission of this disease. Here we identify a novel gene in P. falciparum that when genetically silenced reduces gametocyte production by a factor of 6, and when complemented up-regulates gametocyte-specific gene transcription.
- Published
- 2005
- Full Text
- View/download PDF
88. A novel Plasmodium falciparum ring stage protein, REX, is located in Maurer's clefts.
- Author
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Hawthorne PL, Trenholme KR, Skinner-Adams TS, Spielmann T, Fischer K, Dixon MW, Ortega MR, Anderson KL, Kemp DJ, and Gardiner DL
- Subjects
- Animals, Antibodies, Protozoan, Base Sequence, DNA, Protozoan genetics, Erythrocytes parasitology, Gene Expression Regulation, Developmental, Genes, Protozoan, Humans, Malaria, Falciparum parasitology, Organelles parasitology, Plasmodium falciparum genetics, Plasmodium falciparum growth & development, Plasmodium falciparum immunology, Protozoan Proteins genetics, Protozoan Proteins immunology, RNA, Messenger genetics, RNA, Messenger metabolism, RNA, Protozoan genetics, RNA, Protozoan metabolism, Plasmodium falciparum metabolism, Protozoan Proteins metabolism
- Abstract
The asexual stages of the malaria parasite Plasmodium falciparum develop inside erythrocytes of the human host. Erythrocytes are highly specialized cells lacking organelles and trafficking machinery. The parasite must therefore establish its own transport system to export proteins and waste and import nutrients. A number of parasite-derived structures, implicated in trafficking, appear in the infected red blood cell at the late ring stage. We have identified a novel gene transcribed in ring stage parasites coding for a protein designated the ring exported protein, REX. REX is located in a red cell modification known as the Maurer's clefts, which are parasite induced structures implicated in trafficking of parasite proteins to the red blood cell surface. REX contains predicted coiled-coil regions and a region with similarity to a domain in vesicle-tethering proteins. REX persists in Maurer's clefts throughout the infection of the erythrocyte, where it may play a role in the biogenesis and/or function of this organelle.
- Published
- 2004
- Full Text
- View/download PDF
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