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Gilberger Group

Cell Biology of Human Parasites

Prof. Dr. Tim Gilberger

Group Leader

+49 40 8998 87600
tim.gilberger@cssb-hamburg.de

Home Institute

Bernhard Nocht Institute for Tropical Medicine
www.bnitm.de

Universität Hamburg
www.uni-hamburg.de

My laboratory is interested in the invasion, transformation and egress of human erythrocytes by the malaria parasite Plasmodium falciparum. These biological processes are crucial for survival of parasites in the human system and responsible for all clinical symptoms. We are exploiting reverse genetics, bioinformatics and biochemical approaches to explore these cell biological aspects.

Research Projects

PREVIOUS AND CURRENT RESEARCH

Malaria causes devastation and misery worldwide responsible for the deaths of about 500,000 people every year. Despite its impact on global health, no effective vaccine is established, few drugs are available and resistance is emerging. New therapeutics are therefore urgently needed. The publication of Plasmodium sp. genomes, transcriptomes and proteomes and the emerging possibilities for the genetic modification of the parasite provide the research community with exciting new possibilities in fighting of this disease. However, new treatments have yet to arise and there are still multiple “black boxes” in the complex life cycle of the parasite that are beyond our current knowledge.

P1 RED BLOOD CELL INVASION

P1 Red Blood Cell Invasion

The fast and efficient invasion of human erythrocytes is mandatory for the survival and massive multiplication of the malaria parasite in the host. Host cell invasion is therefore the beginning of the vicious life cycle of the parasite. It is powered by an unknown number of proteins mediating cell adhesion and motility. These proteins are of high interest in drug and vaccine development because interference with this crucial biological process might disrupt the parasite life cycle. Key questions driving this project are: How many parasite proteins are involved in invasion? What is their precise role during this process? And: How can we undermine their function to abrogate cell invasion? The objective of our research is to identify and validate novel key players in erythrocyte invasion in order to deepen our understanding of this fundamental biological process and to identify novel therapeutic targets.

P2 RED BLOOD CELL MODIFICATIONS AND PROTEIN EXPRESSION (Dr. Anna Bachmann)

This project is focused on transcriptomic studies and cell biology approaches to investigate variant surface antigens (VSA) of the human malaria parasite. The malaria parasite manipulates infected red blood cells (iRBCs) such that they stick to the walls of small blood vessels, thereby disturbing the microcirculation and causing severe organ dysfunction. Therefore, VSA mediating cytoadherence of iRBCs are accepted to be the major pathogenicity factor during malaria disease. Studying the expression profile of all VSA families in parallel and especially focusing on patient isolates and samples from large cohort studies we are trying to elucidate the clinical relevance and expression dynamics of VSA during infection.

P3 RED BLOOD CELL EGRESS (Dr. Paul-Christian Burda)

P3 Red Blood Cell Egress

The release of the malaria parasite from its host cell into the bloodstream is a process termed egress. It allows the freshly formed parasites to escape their host cell and to actively invade new red blood cells, amplifying the infection. Like the host cell invasion process it is tightly orchestrated and relies on an unknown number of parasite proteins involving phospholipases, which are involved in membrane disruption processes. In this project, we perform a systematic functional analysis of this gene family during development of the malaria parasite in red blood cells and aim to identify those phospholipases that are enabling the parasite to escape its old host cell. We are also interested in the identification of additional egress factors using organelle specific proximity-based biotinylation techniques.

Research Team

10

Group Leader

Prof. Dr. Tim Gilberger
Phone:+49 40 8998 87600

E-Mail

PhD Student

Arne Alder
Phone:+49 40 8998 87602

E-Mail

Scientific Staff

Dr. Anna Bachmann
Phone:+49 40 42818439

E-Mail

Scientific Staff

Dr. Paul-Christian Burda
Phone:+49 40 8998 87602

E-Mail

Technical Staff

Sarah Lemcke
Phone:+49 40 8998 87602

E-Mail

PhD Student

Emma Pietsch
Phone:+49 40 8998 87602

Scientific Staff

Dr. Jan Strauss
Phone:+49 40 8998 87603

E-Mail

Technical Staff

Heidrun von Thien
Phone:+49 40 42818241

E-Mail

PhD Student

Jan Stephan Wichers
Phone:+49 40 42818241

E-Mail

Master Student

Aimo Zuborg
Phone:+49 40 8998 87602

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Publications

2019

Wichers JS, Scholz JAM, Strauss J, Witt S, Lill A, Ehnold LI, Neupert N, Liffner B, Lühken R, Petter M, Lorenzen S, Wilson DW, Löw C, Lavazec C, Bruchhaus I, Tannich E, Gilberger TW, Bachmann A (2019) Dissecting the Gene Expression, Localization, Membrane Topology, and Function of the Plasmodium falciparum STEVOR Protein Family. MBio. 10. pii: e01500-19. doi: 10.1128/mBio.01500-19.

Patel A, Perrin AJ, Flynn HR, Bisson C, Withers-Martinez C, Treeck M, Flueck C, Nicastro G, Martin SR, Ramos A, Gilberger TW, Snijders AP, Blackman MJ, Baker  DA (2019) Cyclic AMP signalling controls key components of malaria parasite host cell invasion machinery. PLoS Biol. 10;17(5):e3000264. doi: 10.1371/journal.pbio.3000264.

Masch A, Nasereddin A, Alder A, Bird MJ, Schweda SI, Preu L, Doerig C, Dzikowski R, Gilberger TW, Kunick C (2019) Structure-activity relationships in a series of antiplasmodial thieno[2,3-b]pyridines. Malar J. 18: 89. doi: 10.1186/s12936-019-2725-y.

2017

Kumar S, Kumar M, Ekka R, Dvorin JD, Paul AS, Madugundu AK, Gilberger T, Gowda H, Duraisingh MT, Keshava Prasad TS, Sharma P (2017) PfCDPK1 mediated signaling in erythrocytic stages of Plasmodium falciparum. Nat Commun. 8:63. doi: 10.1038/s41467-017-00053-1

2016

Prinz B, Harvey KL, Wilcke L, Ruch U, Engelberg K, Biller L, Lucet I, Erkelenz S, Heincke D, Spielmann T, Doerig C, Kunick C, Crabb BS, Gilson PR, Gilberger TW (2016) Hierarchical phosphorylation of apical membrane antigen 1 is required for efficient red blood cell invasion by malaria parasites. Sci Rep. 6:34479. doi: 10.1038/srep34479.

Engelberg K, Ivey FD, Lin A, Kono M, Lorestani A, Faugno-Fusci D, Gilberger TW, White M, Gubbels MJ (2016) A MORN1-associated HAD phosphatase in the basal complex  is essential for Toxoplasma gondii daughter budding. Cell Microbiol. 18:1153-71. doi: 10.1111/cmi.12574.

Kono M, Heincke D, Wilcke L, Wong TW, Bruns C, Herrmann S, Spielmann T, Gilberger TW (2016) Pellicle formation in the malaria parasite. J Cell Sci. 129: 673-80. doi: 10.1242/jcs.181230.

2015

Spielmann T, Gilberger TW (2015) Critical Steps in Protein Export of Plasmodium falciparum Blood Stages. Trends Parasitol. 10:514-525. doi: 10.1016/j.pt.2015.06.010.

Paul AS, Saha S, Engelberg K, Jiang RH, Coleman BI, Kosber AL, Chen CT, Ganter M, Espy N, Gilberger TW, Gubbels MJ, Duraisingh MT (2015) Parasite Calcineurin Regulates Host Cell Recognition and Attachment by Apicomplexans. Cell Host Microbe. 18: 49-60. doi: 10.1016/j.chom.2015.06.003.

Wetzel J, Herrmann S, Swapna LS, Prusty D, John Peter AT, Kono M, Saini S, Nellimarla S, Wong TW, Wilcke L, Ramsay O, Cabrera A, Biller L, Heincke D, Mossman K, Spielmann T, Ungermann C, Parkinson J, Gilberger TW (2015) The role of palmitoylation for protein recruitment to the inner membrane complex of the malaria parasite. J Biol Chem. 290:1712-28. doi: 10.1074/jbc.M114.598094.

2014

Kumar P, Tripathi A, Ranjan R, Halbert J, Gilberger T, Doerig C, Sharma P (2014) Regulation of Plasmodium falciparum development by calcium-dependent protein kinase 7 (PfCDPK7). J Biol Chem. 289:20386-95. doi: 10.1074/jbc.M114.561670.

2013

Tomlins A, Ben-Rached F, Williams R, Proto W, Coppens I, Ruch U, Gilberger T, Coombs G, Mottram J, Müller S, Langsley G (2013) Plasmodium falciparum ATG8 implicated in both autophagy and apicoplast formation. Autophagy. 9: 1540-52.

Heiber A, Kruse F, Pick C, Grüring C, Flemming S, Oberli A, Schoeler H, Retzlaff S, Mesén-Ramírez P, Hiss J, Kadekoppala M, Hecht L, Holder AA, Gilberger T, Spielmann T (2013) Identification of new PNEPs indicates a substantial non-PEXEL exportome and underpins common features in Plasmodium falciparum protein export. PLoS Pathog. 9: e1003546.

Kono M, Prusty D, Parkinson J, Gilberger T (2013) The apicomplexan inner membrane complex. Front Biosci. 18: 982-92.

Dahan-Pasternak N, Nasereddin A, Kolevzon N, Pe'er M, Wong W, Shinder V, Turnbull L, Whitchurch C, Elbaum M, Gilberger T, Yavin E, Baum J, Dzikowski R, (2013) PfSec13 is an unusual chromatin associated nucleoporin of Plasmodium falciparum, which is essential for parasite proliferation in human erythrocytes. J Cell Sci. 126: 3055-69.

Engelberg K, Paul A, Prinz B, Kono M, Ching W, Heincke D, Dobner T, Spielmann T, Duraisingh M, Gilberger T (2013) Specific phosphorylation of the PfRh2b invasion ligand of Plasmodium falciparum. Biochem J. 452: 457-66.

Mueller C, Kalges N, Cabrera A, Gilberger T, Dubremetz J, Soldati-Favre D (2013) Apical positioning of rhoptries is mediated by palmitoylated ARO and is essential for Toxoplasma host cell invasion but not egress. Cell Host Microbes. 13: 289-301.

2012

Cabrera A, Herrmann S, Warszta D, Santos JM, John Peter AT, Kono M, Debrouver S, Jacobs T, Spielmann T, Ungermann C, Soldati-Favre D, Gilberger T (2012) Dissection of minimal sequence requirements for rhoptry membrane targeting in the malaria parasite. Traffic. 13: 1335-50.

Kono M, Herrmann S, Loughran NB, Cabrera A, Engelberg K, Lehmann C, Sinha D, Prinz B, Ruch U, Heussler V, Spielmann T, Parkinson J, Gilberger T (2012) Evolution and architecture of the inner membrane complex in asexual and sexual stages of the malaria parasite. Mol Biol Evol. 29: 2113-32.

Hoeijmakers W, Salcedo-Amaya A, Smits A, Françoijs K, Treeck M Gilberger, T Stunnenberg, H Bártfai, R (2012) H2A.Z/H2B.Z double-variant nucleosomes inhabit the AT-rich promoter regions of the Plasmodium falciparum genome. Mol Micro. 87: 1061-73.

Yahata K, Treeck M, Culleton R, Gilberger T, Kaneko O (2012) Time-lapse imaging of red blood cell invasion by rodent malaria parasit. PlosOne. 7: e50780.      

Grüring C, Heiber A, Kruse F, Flemming S, Franci G, Colombo S, Fasana E, Schöler H, Borgese N, Stunnenberg H, Przyborski J, Gilberger T, Spielmann T (2012) Common principles in malaria protein export. Cell Host Microbes. 12: 417-29.

Dixon M, Dearnley M, Hanssen E, Gilberger T, Tilley L (2012) Shape-shifting gametocytes: how and why does P. falciparum go banana-shaped? Trends Parasitol. 28: 471-8.

Thomas D, Ahmed A, Gilberger T, Sharma P (2012) Regulation of Plasmodium falciparum Gildeosome Associated Protein 45 (GAP45) by phosphorylation. PloSOne. 7, e35855.

Deshmukh AS, Srivastava S, Herrmann S, Gupta A, Mitra P, Gilberger T, Dhar S (2012) The role of N-terminus of Plasmodium falciparum ORC1 in telomeric localization and var gene silencing. Nucleic Acid Res. 40: 5313-31.

2011

Bachmann A, Predehl S, May J, Harder S, Burchard GD, Gilberger T, Tannich E, Bruchhaus I (2011) Highly co-ordinated var gene expression and switching in clinical Plasmodium falciparum isolates from non-immune malaria patients. Cell Microbiol. 13: 1397-409.

malERA Consultative Group on Basic Science and Enabling Technologies (2011) A research agenda for malaria eradication: basic science and enabling technologies. PLoS Med. 8: e1000399. Review.

Grüring C, Heiber A, Ungefehr U, Gilberger T, Spielmann T* (2011) Development and Host Cell Modifications of Plasmodium falciparum Blood Stages in 4D. Nat. Comm. 2, 165. *Corresponding authors.

2010

Bártfai R, Hoeijmakers W, Salcedo-Amaya A, Smits A, Janssen-Megens E, Kaan A, Treeck M, Gilberger T, Françoijs K, Stunnenberg H (2010) H2A.Z demarcates intergenic regions of the Plasmodium falciparum epigenome that are dynamically marked by H3K9ac & H3K4me3. PloS Pathogens 6:e1001223.

Leykauf K*, Treeck M*, Gilson P, Nebl T, Braulke T, Cowman A, Gilberger T**, Crabb** B (2010) Protein kinase A-dependent phosphorylation of apical membrane antigen plays an important role in erythrocyte invasion by the malaria parasite PloS Pathogens 6: e1000941. *Joint first authors, **Corresponding authors

Weiss R, Gabler M, Jacobs T, Gilberger T, Thalhamer J, Scheiblhofer S (2010) Differential effects of C3d on the immunogenicity of gene gun vaccines encoding Plasmodium falciparum and Plasmodium berghei MSP1(42). Vaccine 28: 4515-22.

Schottelius J, Gilberger T, Ehrhardt S, Burchard G (2010) Plasmodium knowlesi: cause of naturally acquired malaria in humans. Dtsch. Med. Wochenschr. 135: 297-300.

Hu* G, Cabrera* A, Mok S, Kono M, Cheemadan S, Haase S, Chaal BK, Wastuwidyaningtyas D, Spielmann T, Preiser P, Gilberger** T, Bozdech** Z (2010) Plasmodium falciparum protein function predicted by a high confidence interactome network.  Nat. Biotechnol. 28:91-98. *Joint first authors, **Corresponding authors.

Spielmann T, Gilberger T (2010) Protein export in malaria parasites: do multiple export motifs add up to multiple export pathways? Trends Parasitol., 26: 6-10.

2009

Treeck M, Tamborrini M, Daubenberger C, Gilberger T, Voss T (2009) Caught in action: mechanistic insight into antibody-mediated inhibition of Plasmodium merozoite invasion. Trends Parasitol. 25: 494-497.

Treeck M, Zacherl S, Herrmann S, Haase S Engelberg K, Kono M, Struck N, Cabrera A, Frischknecht F Miura, K Spielmann, T Gilberger, T (2009) Functional analysis of the leading malaria vaccine candidate AMA-1 reveals an essential role for the cytoplasmic domain in the invasion process. PloS Pathogens 5: e1000322.

Wickramarachchi T, Cabrera A, Sinha D, Dhawan S, Chandran T, Devi Y, Kono M, Spielmann T, Chauhan* VS, Gilberger* T, Mohmmed* A (2009) A Novel Plasmodium falciparum Erythrocyte Binding Protein Associated with the Merozoite Surface, PfDBLMSP. Int. J. Parasitol. 39: 763-773 *Corresponding authors.

Haase S, Herrmann S, Langer C, Treeck M, Cabrera A, Jansen P, Struck N, Kono M, Stunnenberg H, Gilberger* T, Spielmann* T (2009) A short motif necessary for export links REX2 and SBP1 with the PEXEL pathway in P. falciparum. Mol. Micro. 71: 1003-1017. * Corresponding authors.

2008

Baum J, Gilberger T, Frischknecht F, Meissner M (2008): Malaria parasite host-cell invasion: insights from across the Plasmodium lifecycle and Toxoplasma (Review). Trends Parasitol. 24: 557-563.

Struck N, Herrmann S, Langer C, Krueger A, Foth BJ, Engelberg K, Cabrera AL, Haase S, Treeck M, Marti M, Cowman AF, Spielmann T, Gilberger T (2008) Plasmodium falciparum possesses two GRASP proteins that are differentially targeted to the Golgi complex via a higher- and lower-eukaryote-like mechanism. J. Cell Sci. 121: 2123-29.

Struck N, Herrmann S, Schmuck-Barkmann I, de Souza Diaz S, Haase S, Cabrera AL, Treeck M, Bruns C, Langer C, Cowman AF, Marti M, Spielmann T, Gilberger T (2008) Restricted ER export competence and Spatial dissection of the cis- and Trans-Golgi compartments in the malaria parasite Plasmodium falciparum. Mol. Micro. 67: 1320-30.

Haase S, Cabrera A, Langer C, Treeck T, Struck N, Herrmann S, Jansen PW, Bruchhaus I, Bachmann A, Dias S, Cowman AF, Stunnenberg HG, Spielmann T, Gilberger, T (2008) Characterization of a conserved rhoptry-associated leucine zipper-like protein in the malaria parasite Plasmodium falciparum. Infect. Immun. 76: 879-887.

2007

Jackson KE, Spielmann T, Hanssen E, Adisa A, Separovic F, Dixon MW, Trenholme KR, Hawthorne PL, Gardiner DL, Gilberger T, Tilley L (2007) Selective permeabilization of the host cell membrane of Plasmodium falciparum-infected red blood cells with streptolysin O and equinatoxin II. Biochem J. 403: 167-175.

Spielmann T, Gilberger T (2007) New therapeutic approaches for malaria: molecular aspects of erythrocyte invasion. Dtsch Med Wochenschr. 132: 2383-6.

2006

O´Donnell R, Hackett F, Howell SA, Treeck M, Struck NS, Krnajski Z, Withers-Martinez C, Gilberger* T, Blackmann* MJ (2006) Intermembrane proteloysis mediates shedding of a key adhesin during erythrocyte invasion by the malaria parasite. J Cell Biol 174: 1023-33. * Corresponding authors.

Eschbach ML, Müller IB, Gilberger T, Walter RD, Wrenger C (2006) The human malaria parasite Plasmodium falciparum expresses an atypical N-terminally extended pyrophosphokinase with specificity for thiamine. Biol. Chem. 387: 1583-91.

Treeck M, Struck NS, Haase S, Langer C, Herrmann S, Healer J, Cowman AF, Gilberger T (2006) A conserved region in the EBL-proteins is implicated in microneme targeting of the malaria parasite Plasmodium falciparum. J. Biol. Chem. 281: 31995-2003.

Baum J, Richard D, Healer J, Rug M, Krnajski Z, Gilberger T, Green JL, Holder AA, Cowman A (2006) A conserved molecular motor drives cell invasion and gliding motility across malaria lifecycle stages and other apicomplexan parasites. J. Biol. Chem. 281: 5197-208.

2005

Struck NS, de Souza Dias S, Langer C, Marti M, Pearce JA, Cowman AF, Gilberger T (2005) Re-defining the Golgi complex in P. falciparum using the novel Golgi marker PfGRASP. J. Cell Sci. 118: 5603-13.

Haider N, Eschbach ML, Dias S, Gilberger T, Walter RD, Lüersen K (2005) The spermidine synthase of the malaria parasite Plasmodium falciparum: molecular and biochemical characterization of the polyamine synthesis enzyme. Mol. Biochem. Parasitol.142: 224-36.

2004

Crabb BS, Rug M, Gilberger T, Thompson JK, Triglia T, Maier AG, Cowman AF (2004) Transfection of the human malaria parasite Plasmodium falciparum. Methods Mol. Biol. 270: 263-76.

2003

Gilberger T, Thompson JK, Reed MB, Good RT, Cowman AF (2003) The cytoplasmic domain of the Plasmodium falciparum ligand EBA-175 is essential for invasion but not protein trafficking. J Cell Biol 162: 317-27.

Gilberger T, Thompson JK, Triglia T, Good RT, Duraisingh MT, Cowman AF (2003) A novel erythrocyte binding antigen-175 paralogue from Plasmodium falciparum defines a new trypsin-resistant receptor on human erythrocytes. J. Biol. Chem.  278:14480-6.

2002

Krnajski Z, Gilberger T, Walter RD, Cowman AF, Muller S (2002) Thioredoxin reductase is essential for the survival of Plasmodium falciparum erythrocytic stages. J. Biol. Chem.  277: 25970-5.

2001

Muller S, Gilberger T, Krnajski Z, Luersen K, Meierjohann S, Walter RD (2001)  Thioredoxin and glutathione system of malaria parasite Plasmodium falciparum. Protoplasma 217: 43-9. Review.

Krnajski Z, Gilberger T, Walter RD, Muller S (2001) The malaria parasite Plasmodium falciparum possesses a functional thioredoxin system. Mol. Biochem. Parasitol. 112: 219-28.

Krause T, Luersen K, Wrenger C, Gilberger T, Muller S, Walter RD (2001) The ornithine decarboxylase domain of the bifunctional ornithine decarboxylase/S-adenosylmethionine decarboxylase of Plasmodium falciparum: recombinant expression and catalytic properties of two different constructs. Biochem. J. 352: 287-92.

2000

Krnajski Z, Gilberger T, Walter RD, Muller S (2000) Intersubunit interactions in Plasmodium falciparum thioredoxin reductase. J. Biol. Chem. 275: 40874-8.

Gilberger T, Schirmer RH, Walter RD, Muller S (2000) Deletion of the parasite-specific insertions and mutation of the catalytic triad in glutathione reductase from chloroquine-sensitive Plasmodium falciparum 3D7. Mol. Biochem. Parasitol. 107:169-79.

1999

Wang PF, Arscott LD, Gilberger T, Muller S, Williams CH Jr. (1999) Thioredoxin reductase from Plasmodium falciparum: evidence for interaction between the C-terminal cysteine residues and the activesite disulfide-dithiol. Biochemistry 38: 3187-96.

1998

Gilberger T, Bergmann B, Walter RD, Muller S (1998) The role of the C-terminus for catalysis of the large thioredoxin reductase from Plasmodium falciparum. FEBS Lett. 425: 407-10.

1997

Gilberger TW, Walter RD, Muller S (1997) Identification and characterization of the functional amino acids at the active site of the large thioredoxin reductase from Plasmodium falciparum. J. Biol. Chem. 272: 29584-9.

Muller S, Gilberger T, Fairlamb AH, Walter RD (1997) Molecular characterization and expression of Onchocerca volvulus glutathione reductase. Biochem. J. 325: 645-51.

1996

Muller S, Gilberger T, Farber PM, Becker K, Schirmer RH, Walter RD (1996) Recombinant putative glutathione reductase of Plasmodium falciparum exhibits thioredoxin reductase activity.  Mol. Biochem. Parasitol. 80: 215-9.