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Pathogen-host cell interactions during the liver stage of Plasmodium parasites

English title Pathogen-host cell interactions during the liver stage of Plasmodium parasites
Applicant Heussler Volker
Number 159519
Funding scheme Project funding (Div. I-III)
Research institution Institut für Zellbiologie Departement Biologie Universität Bern
Institution of higher education University of Berne - BE
Main discipline Experimental Microbiology
Start/End 01.08.2015 - 31.12.2018
Approved amount 646'888.00
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All Disciplines (6)

Discipline
Experimental Microbiology
Zoology
Immunology, Immunopathology
Medical Microbiology
Tropical Medicine
Cellular Biology, Cytology

Keywords (9)

intravital imaging; autophagy; lipases; Liver stage; parasite egress; host-pathogen interaction; Malaria; signalling; CRISPR/Cas9

Lay Summary (German)

Lead
Malaria ist immer noch die wichtigste parasitäre Tropenkrankheit weltweit. Nach dem Stich einer infizierten Anophelesmücke gelangen die Erreger schnell in die Blutbahn und dann in die Leber, wo sie sich zunächst unbemerkt vermehren. Wir untersuchen wie der Parasit sich in seiner Wirtszelle etabliert und wie er nach der Leberphase in die Blutphase wechselt.
Lay summary

 Inhalt und Ziel des Forschungsprojektes

Wenn Malaria-Parasiten von einer infizierten Anophelesmücke übertragen werden, verweilen sie nur für kurze Zeit im Blut. Um dem Immunsystem zu entgehen, dringen sie schnell in Leberzellen ein. Das stellt den Parasiten aber vor eine Reihe von Problemen: die Wirtszelle selbst hat die Möglichkeit den Parasiten anzugreifen und zu verdauen in einem Prozess den wir selektive Autophagie nennen. Ausserdem müssen die Parasiten am Ende der Leberphasenentwicklung die Leberzelle verlassen und durch die Blutgefässwand zu den roten Blutzellen gelangen, die dann infiziert werden können. Wir versuchen zu verstehen, wie die Parasiten sich der Reaktion der Wirtszellen entziehen und wie sie dann die Wirtszellen manipulieren, um in den Blutstrom zu gelangen.

Wissenschaftlicher und gesellschaftlicher Kontext des Forschungsprojektes

Dieses in der Grundlagenforschung angesiedelte Projekt befasst sich mit der Interaktion von Parasiten und ihren Wirtszellen. Nur wenn wir die Biologie des Malaria-Erregers verstehen, können wir neue, innovative Massnahmen zu seiner Bekämpfung finden. Im Hinblick auf die sich schnell ausbreitenden Resistenzen gegen die heute verwendeten Malariamedikamente und die Tatsache, dass es noch immer keine wirksame Impfung gegen diese Infektion gibt, sind solche Ansätze von grosser Bedeutung.

 

Direct link to Lay Summary Last update: 09.07.2015

Responsible applicant and co-applicants

Employees

Publications

Publication
Plasmodium berghei sporozoites in nonreplicative vacuole are eliminated by a PI3P ‐mediated autophagy‐independent pathway
Bindschedler Annina, Wacker Rahel, Egli Jessica, Eickel Nina, Schmuckli-Maurer Jacqueline, Franke-Fayard Blandine M., Janse Chris J., Heussler Volker T. (2021), Plasmodium berghei sporozoites in nonreplicative vacuole are eliminated by a PI3P ‐mediated autophagy‐independent pathway, in Cellular Microbiology, 1-16.
A Plasmodium cysteine protease required for efficient transition from the liver infection stage
Putrianti Elyzana Dewi, Schmidt-Christensen Anja, Heussler Volker, Matuschewski Kai, Ingmundson Alyssa (2020), A Plasmodium cysteine protease required for efficient transition from the liver infection stage, in {PLOS} Pathogens, 16(9), 1008891-1008891.
Hijacking of the host cell Golgi by Plasmodium liver stage parasites
de Niz Mariana, Kaiser Gesine, Zuber Benoit, Heo Won Do, Heussler Volker T, Nersesian Carolina Agop (2020), Hijacking of the host cell Golgi by Plasmodium liver stage parasites, in bioRxiv, 1-31.
Targeting Plasmodium Plasmepsin V: Hitting Two Birds with One Stone
Brancucci N.M.B., Heussler V.T., Grüring C. (2020), Targeting Plasmodium Plasmepsin V: Hitting Two Birds with One Stone, in Trends in Parasitology, 36(2), 85-87.
Activation of the macroautophagy pathway by Yersinia enterocolitica promotes intracellular multiplication and egress of yersiniae from epithelial cells
Lopez Maria Jose Valencia, Schimmeck Hanna, Gropengießer Julia, Middendorf Lukas, Quitmann Melanie, Schneider Carola, Holstermann Barbara, Wacker Rahel, Heussler Volker, Reimer Rudolph, Aepfelbacher Martin, Ruckdeschel Klaus (2019), Activation of the macroautophagy pathway by Yersinia enterocolitica promotes intracellular multiplication and egress of yersiniae from epithelial cells, in Cellular Microbiology, 13046-13046.
Deciphering host lysosome-mediated elimination of Plasmodium berghei liver stage parasites
Niklaus L., Agop-Nersesian C., Schmuckli-Maurer J., Wacker R., Gruenig V., Heussler V. T. (2019), Deciphering host lysosome-mediated elimination of Plasmodium berghei liver stage parasites, in Scientific Reports, 9(1), 1-15.
Genome-Scale Identification of Essential Metabolic Processes for Targeting the Plasmodium Liver Stage
Stanway R.R., Bushell E., Chiappino-Pepe A., Roques M., Sanderson T., Franke-Fayard B., Caldelari R., Golomingi M., Nyonda M., Pandey V., Schwach F., Chevalley S., Ramesar J., Metcalf T., Herd C., Burda P.-C., Rayner J.C., Soldati-Favre D., Janse C.J., Hatzimanikatis V., Billker O., Heussler V.T. (2019), Genome-Scale Identification of Essential Metabolic Processes for Targeting the Plasmodium Liver Stage, in Cell, 179(5), 1112-1128.
Transcriptome analysis of Plasmodium berghei during exo-erythrocytic development
Caldelari R., Dogga S., Schmid M.W., Franke-Fayard B., Janse C.J., Soldati-Favre D., Heussler V. (2019), Transcriptome analysis of Plasmodium berghei during exo-erythrocytic development, in Malaria Journal, 18(1), 1-20.
Host cell cytosolic immune response during Plasmodium liver stage development
Agop-Nersesian Carolina, Niklaus Livia, Wacker Rahel, Heussler Volker Theo (2018), Host cell cytosolic immune response during Plasmodium liver stage development, in {FEMS} Microbiology Reviews, 42(3), 324-334.
Plasmodium gametocytes display homing and vascular transmigration in the host bone marrow
De Niz M., Meibalan E., Mejia P., Ma S., Brancucci N.M.B., Agop-Nersesian C., Mandt R., Ngotho P., Hughes K.R., Waters A.P., Huttenhower C., Mitchell J.R., Martinelli R., Frischknecht F., Seydel K.B., Taylor T., Milner D., Heussler V.T., Marti M. (2018), Plasmodium gametocytes display homing and vascular transmigration in the host bone marrow, in Science Advances, 4(5), 1-15.
Shedding of host autophagic proteins from the parasitophorous vacuolar membrane of Plasmodium berghei
Agop-Nersesian Carolina, De Niz Mariana, Niklaus Livia, Prado Monica, Eickel Nina, Heussler Volker T. (2017), Shedding of host autophagic proteins from the parasitophorous vacuolar membrane of Plasmodium berghei, in Scientific Reports, 7(1), 2191-2191.
Photosensitized INA-Labelled protein 1 (PhIL1) is novel component of the inner membrane complex and is required for Plasmodium parasite development
Saini Ekta, Zeeshan Mohammad, Brady Declan, Pandey Rajan, Kaiser Gesine, Koreny Ludek, Kumar Pradeep, Thakur Vandana, Tatiya Shreyansh, Katris Nicholas J., Limenitakis Rebecca Stanway, Kaur Inderjeet, Green Judith L., Bottrill Andrew R., Guttery David S., Waller Ross F., Heussler Volker, Holder Anthony A., Mohmmed Asif, Malhotra Pawan, Tewari Rita (2017), Photosensitized INA-Labelled protein 1 (PhIL1) is novel component of the inner membrane complex and is required for Plasmodium parasite development, in Scientific Reports, 7(1), 15577-15577.
Generation of transgenic rodent malaria parasites by transfection of cell culture-derived merozoites
Kaiser Gesine, De Niz Mariana, Burda Paul-Christian, Niklaus Livia, Stanway Rebecca Limenitakis, Heussler Volker (2017), Generation of transgenic rodent malaria parasites by transfection of cell culture-derived merozoites, in Malaria Journal, 16(1), 305-305.
A multistage antimalarial targets the plasmepsins IX and X essential for invasion and egress
Pino Paco, Caldelari Reto, Mukherjee Budhaditya, Vahokoski Juha, Klages Natacha, Maco Bohumil, Collins Christine R., Blackman Michael J., Kursula Inari, Heussler Volker, Brochet Mathieu, Soldati-Favre Dominique (2017), A multistage antimalarial targets the plasmepsins IX and X essential for invasion and egress, in Science, 358(6362), 522-528.
Deletion of the rodent malaria ortholog for falcipain-1 highlights differences between hepatic and blood stage merozoites
Hopp Christine S., Bennett Brandy L., Mishra Satish, Lehmann Christine, Hanson Kirsten K., Lin Jing-wen, Rousseau Kimberly, Carvalho Filomena A., van der Linden Wouter A., Santos Nuno C., Bogyo Matthew, Khan Shahid M., Heussler Volker, Sinnis Photini (2017), Deletion of the rodent malaria ortholog for falcipain-1 highlights differences between hepatic and blood stage merozoites, in PLOS Pathogens, 13(9), e1006586-e1006586.
Manipulation of the Host Cell Membrane during Plasmodium Liver Stage Egress
Burda Paul-Christian, Caldelari Reto, Heussler Volker T. (2017), Manipulation of the Host Cell Membrane during Plasmodium Liver Stage Egress, in mBio, 8(2), 1-12.
Progress in imaging methods: insights gained into Plasmodium biology
De Niz Mariana, Burda Paul-Christian, Kaiser Gesine, del Portillo Hernando A., Spielmann Tobias, Frischknecht Freddy, Heussler Volker T. (2017), Progress in imaging methods: insights gained into Plasmodium biology, in Nature Reviews Microbiology, 15(1), 37-54.
A Plasmodium plasma membrane reporter reveals membrane dynamics by live-cell microscopy
Burda Paul-Christian, Schaffner Marco, Kaiser Gesine, Roques Magali, Zuber Beno\^ıt, Heussler Volker T. (2017), A Plasmodium plasma membrane reporter reveals membrane dynamics by live-cell microscopy, in Scientific Reports, 7(1), 1-14.
The machinery underlying malaria parasite virulence is conserved between rodent and human malaria parasites
Heussler Volker (2016), The machinery underlying malaria parasite virulence is conserved between rodent and human malaria parasites, in Nature communications, 27225796.

Datasets

Transcriptome analysis of Plasmodium berghei during exo-erythrocytic development

Author Caldelari, Reto; Dogga, Sunil; Schmid, Marc W.; Franke-Fayard, Blandine; Janse, Chris J.; Soldati-Favre, Dominique; Heussler, Volker
Publication date 24.12.2019
Persistent Identifier (PID) 10.1186/s12936-019-2968-7
Repository European Nucleotide Archive
Abstract
AbstractBackgroundThe complex life cycle of malaria parasites requires well-orchestrated stage specific gene expression. In the vertebrate host the parasites grow and multiply by schizogony in two different environments: within erythrocytes and within hepatocytes. Whereas erythrocytic parasites are well-studied in this respect, relatively little is known about the exo-erythrocytic stages.Methods In an attempt to fill this gap, genome wide RNA-seq analyses of various exo-erythrocytic stages of Plasmodium berghei including sporozoites, samples from a time-course of liver stage development and detached cells were performed. These latter contain infectious merozoites and represent the final step in exo-erythrocytic development. Results The analysis represents the complete transcriptome of the entire life cycle of P. berghei parasites with temporal detailed analysis of the liver stage allowing comparison of gene expression across the progression of the life cycle. These RNA-seq data from different developmental stages were used to cluster genes with similar expression profiles, in order to infer their functions. A comparison with published data from other parasite stages confirmed stage-specific gene expression and revealed numerous genes that are expressed differentially in blood and exo-erythrocytic stages. One of the most exo-erythrocytic stage-specific genes was PBANKA_1003900, which has previously been annotated as a “gametocyte specific protein”. The promoter of this gene drove high GFP expression in exo-erythrocytic stages, confirming its expression profile seen by RNA-seq. Conclusions The comparative analysis of the genome wide mRNA expression profiles of erythrocytic and different exo-erythrocytic stages could be used to improve the understanding of gene regulation in Plasmodium parasites and can be used to model exo-erythrocytic stage metabolic networks toward the identification of differences in metabolic processes during schizogony in erythrocytes and hepatocytes.

Genome-Scale Identification of Essential Metabolic Processes for Targeting the Plasmodium Liver Stage

Author Stanway, Rebecca R.; Bushell, Ellen; Chiappino-Pepe, Anush; Roques, Magali; Sanderson, Theo; Franke-Fayard, Blandine; Caldelari, Reto; Golomingi, Murielle; Nyonda, Mary; Pandey, Vikash; Schwach, Frank; Chevalley, Séverine; Ramesar, Jai; Metcalf, Tom; Herd, Colin; Burda, Paul-Christian; Rayner, Julian C.; Soldati-Favre, Dominique; Janse, Chris J.; Hatzimanikatis, Vassily; Billker, Oliver; Heussler, Volker T.
Publication date 01.11.2019
Persistent Identifier (PID) 10.1016/j.cell.2019.10.030
Repository GitHub


Genome-Scale Identification of Essential Metabolic Processes for Targeting the Plasmodium Liver Stage

Author Stanway, Rebecca R.; Bushell, Ellen; Chiappino-Pepe, Anush; Roques, Magali; Sanderson, Theo; Franke-Fayard, Blandine; Caldelari, Reto; Golomingi, Murielle; Nyonda, Mary; Pandey, Vikash; Schwach, Frank; Chevalley, Séverine; Ramesar, Jai; Metcalf, Tom; Herd, Colin; Burda, Paul-Christian; Rayner, Julian C.; Soldati-Favre, Dominique; Janse, Chris J.; Hatzimanikatis, Vassily; Billker, Oliver; Heussler, Volker T.
Publication date 01.11.2019
Persistent Identifier (PID) 10.1016/j.cell.2019.10.030
Repository LCSB


Collaboration

Group / person Country
Types of collaboration
Dr. Tobias Spielmann, BNI Hamburg Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
- Exchange of personnel
Prof. Vasilly Hatzmanitakis; EPFL, Lausanne Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
- Exchange of personnel
Prof. Dominique Soldati, Uni Geneva Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
- Exchange of personnel
Dr. Asif Mohmmed, ICGEB New Dehli India (Asia)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
- Exchange of personnel
Prof. Matthias Marti Great Britain and Northern Ireland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
- Exchange of personnel
Prof. Photini Sinnis, New York University United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
- Exchange of personnel
Chris Janse; University of Leiden Netherlands (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
- Exchange of personnel

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
BioMalPar 2018 Individual talk A high-throughput liver stage phenotyping screen of P. berghei knockouts reveals novel insights into Plasmodium metabolism 23.05.2018 Heidelberg, Germany Roques Magali; Heussler Volker; Roques Magali;
BioMalPar 2018 Poster Inverted recruitment of autophagy proteins to the Plasmodium berghei parasitophorous vacuole membrane 23.05.2018 Heidelberg, Germany Heussler Volker;
International Symposium of the SFB 1129 Talk given at a conference Cytosolic immune responses of host hepatocytes against Plasmodium infection and parasite escape mechanisms 18.01.2018 Heidelberg, Germany Heussler Volker;
CSSB symposium 2017 Talk given at a conference A systems biology approach to understand liver stage malaria infection 13.11.2017 Hamburg, Germany Heussler Volker;
Seminar University of Lisbon Individual talk Liver stage malaria parasites escape host cell selective 23.10.2017 Lisbon, Portugal Heussler Volker;
Seminar, Institut für Immunologie Uni Bern Individual talk Plasmodium berghei is a powerful rodent model to study the biology of malaria parasites 11.10.2017 Bern, Switzerland Heussler Volker;
SystemsX.ch conference 2017 Talk given at a conference A systems biology approach to understand liver stage malaria infection 04.09.2017 Zürich, Switzerland Heussler Volker;
Young investigator course in molecular parasitology Individual talk Parasitism as a life style 11.08.2017 Hamburg, Germany Heussler Volker;
Lecture at BoP course Individual talk Plasmodium liver stage biology 02.08.2017 Woods Hole, United States of America Heussler Volker;
meBoP course 2017 Individual talk Plasmodium liver stage 26.07.2017 Bern, Switzerland Heussler Volker;
International Symposium of the SFB 1129 Talk given at a conference Cytosolic immune responses of host hepatocytes against Plasmodium infection and parasite escape mechanisms 20.07.2017 Heidelberg, Germany Heussler Volker;
Gordon Research Conference 2017 Talk given at a conference Single Cell Biology of EEFs 02.07.2017 Les Diablerets, Switzerland Heussler Volker;
BioMalPar 2017 Poster A genome-wide screen reveals genes with key roles in pre-erythrocytic development 29.05.2017 Heidelberg, Germany Heussler Volker;
BioMalPar 2017 Poster Identification of novel PVM proteins using BioID 29.05.2017 Heidelberg, Germany Burda Paul-Christian; Heussler Volker;
BioMalPar Poster Active vascular transmigration of Plasmodium gametocytes across the bone marrow endothelium 29.05.2017 Heidelberg, Germany Heussler Volker;
Indigo Symposium 2017 Talk given at a conference Membrane dynamics in liver stage parasites 23.03.2017 Grenoble, France Heussler Volker;
DGHM annual meeting 2016 Talk given at a conference Cytosolic immune responses of host hepatocytes against Plasmodium infection and parasite escape mechanisms 11.09.2016 Ulm, Germany Heussler Volker;
meBOP course 2016 Individual talk Plasmodium liver stage biology 04.08.2016 Bern, Switzerland Heussler Volker;
Seminar Pasteurinstitut Paris Individual talk Conserved machinery underlying malaria parasite virulence in rodents and humans 16.06.2016 Paris, France Heussler Volker;
BioMalPar 2016 Poster Double-fluorescent parasites reveal interaction of membrane systems in Plasmodium liver stages 18.05.2016 Heidelberg, Germany Heussler Volker; Kaiser Gesine; Burda Paul-Christian;
BioMalPar 2016 Individual talk Conserved dynamics of Plasmodium gametocyte localization in the bone marrow of humans and mice 18.05.2016 Heidelberg, Germany Heussler Volker;
Seminar at Tropical Institute Basel Individual talk Cytosolic immune responses of host hepatocytes against Plasmodium infection and parasite escape mechanisms 13.04.2016 Basel, Switzerland Heussler Volker;
Seminar at Theodor Kocher Institute Individual talk Cytosolic immune responses of host hepatocytes against Plasmodium infection and parasite escape mechanisms 04.04.2016 Bern, Switzerland Heussler Volker;
Malaria Symposium 2016 Talk given at a conference Starvation supports Plasmodium development in infected hepatocytes in vivo 16.02.2016 New Delhi, India Heussler Volker;


Communication with the public

Communication Title Media Place Year
Media relations: print media, online media Berner Forschende sind dem Malaria-Parasiten auf der Spur teleBasel German-speaking Switzerland 2018
Media relations: print media, online media Berner Forscher sind den Malaria-Parasiten auf der Spur Der Bund German-speaking Switzerland 2018
Media relations: print media, online media Brutstätte des Malaria-Parasiten interpharma German-speaking Switzerland 2018
Media relations: radio, television Rätsel um Malaria gelöst Radio Bern German-speaking Switzerland 2018
Media relations: print media, online media Rätsel um Malaria-Parasit gelöst Universität Bern Medienmitteilung German-speaking Switzerland International 2018
Media relations: print media, online media Wie der Malaria-Parasit im Knochenmark heranreift NZZ German-speaking Switzerland International 2018
Media relations: print media, online media A new weapon against malaria press release Uni Geneva Western Switzerland International 2017
Media relations: print media, online media Eine neue Waffe im Kampf gegen Malaria Medienmitteilung Uni Bern German-speaking Switzerland 2017
Media relations: print media, online media Recycling in lebenden Zelle NZZ German-speaking Switzerland 2016

Associated projects

Number Title Start Funding scheme
145013 Multimode Live Imaging - University of Bern (MLI-be) 01.04.2013 R'EQUIP
140691 Pathogen-host cell interactions during the liver stage of Plasmodium parasites 01.08.2012 Project funding (Div. I-III)
182465 Pathogen-host cell interactions during the liver stage of Plasmodium parasites III 01.01.2019 Project funding (Div. I-III)
150824 White-Laser Confocal Microscopy: Modular and Sensitive Multi-channel Analysis 01.12.2013 R'EQUIP
177096 A high content confocal microscope for fast 3D imaging of living samples 01.10.2018 R'EQUIP

Abstract

During the current funding period, we could show that egress of Plasmodium parasites is initiated by the activation of a parasite-derived phospholipase (PbPL for P. berghei phospholipase) that is involved in the destruction of the parasitophorous vacuole membrane (PVM). Furthermore, we could define a new host cell autophagy pathway that is involved in the recognition and labeling of the PVM in infected hepatocytes. For the next funding period, we propose to concentrate on these two successfully initiated projects, both centered on the role of the PVM during parasite development and egress. Parasite egress from hepatocytes is clearly separated into two phases. One is the destruction of the PVM, liberating merozoites into the cytosol of the host cell. This phase is followed by the transport of merozoites, within host cell-derived vesicles (merosomes), into the blood stream where they are liberated from the host cell to infect red blood cells (RBCs). To decipher parasite egress, we will concentrate on the molecular events relating to PVM rupture. It appears that phospholipases play a crucial role in this event and we have identified putative phospholipases that localize to the PVM at the end of liver stage development. Their roles will be investigated using reverse genetics. Interaction partners of the PVM-localized phospholipases will be identified to understand how the activity of phospholipases is regulated. In addition we will continue to further analyze the activation of PbPL and in particular whether proteases play a role in this process. For the second part of this project, we propose to further investigate the role of host cell autophagy in parasite elimination as well as strategies used by the parasite to escape this host cell response and even to use it as an additional source of nutrients. In particular, we plan to manipulate autophagy pathways by genetic modification of the host cell using the powerful CRISPR/Cas9 technology.
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