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Publications (5 of 5) Show all publications
Hillier, C., Pardo, M., Yu, L., Bushell, E., Sanderson, T., Metcalf, T., . . . Choudhary, J. S. (2019). Landscape of the Plasmodium Interactome Reveals Both Conserved and Species-Specific Functionality. Cell reports, 28(6), 1635-1647
Open this publication in new window or tab >>Landscape of the Plasmodium Interactome Reveals Both Conserved and Species-Specific Functionality
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2019 (English)In: Cell reports, ISSN 2211-1247, E-ISSN 2211-1247, Vol. 28, no 6, p. 1635-1647Article in journal (Refereed) Published
Abstract [en]

Malaria represents a major global health issue, and the identification of new intervention targets remains an urgent priority. This search is hampered by more than one-third of the genes of malaria-causing Plasmodium parasites being uncharacterized. We report a large-scale protein interaction network in Plasmodium schizonts, generated by combining blue native-polyacrylamide electrophoresis with quantitative mass spectrometry and machine learning. This integrative approach, spanning 3 species, identifies > 20,000 putative protein interactions, organized into 600 protein clusters. We validate selected interactions, assigning functions in chromatin regulation to previously unannotated proteins and suggesting a role for an EELM2 domain-containing protein and a putative microrchidia protein as mechanistic links between AP2-domain transcription factors and epigenetic regulation. Our interactome represents a high-confidence map of the native organization of core cellular processes in Plasmodium parasites. The network reveals putative functions for uncharacterized proteins, provides mechanistic and structural insight, and uncovers potential alternative therapeutic targets.

Place, publisher, year, edition, pages
Elsevier, 2019
Keywords
Plasmodium, blue native-PAGE, interactome, protein-protein interactions, interaction network, malaria, Plasmodium falciparum, Plasmodium berghei, Plasmodium knowlesi
National Category
Cell Biology
Identifiers
urn:nbn:se:umu:diva-162665 (URN)10.1016/j.celrep.2019.07.019 (DOI)000478978200023 ()31390575 (PubMedID)
Available from: 2019-09-04 Created: 2019-09-04 Last updated: 2019-09-04Bibliographically approved
Howick, V. M., Russell, A. J. C., Andrews, T., Heaton, H., Reid, A. J., Natarajan, K., . . . Lawniczak, M. K. N. (2019). The Malaria Cell Atlas: Single parasite transcriptomes across the complete Plasmodium life cycle. Science, 365(6455), Article ID eaaw2619.
Open this publication in new window or tab >>The Malaria Cell Atlas: Single parasite transcriptomes across the complete Plasmodium life cycle
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2019 (English)In: Science, ISSN 0036-8075, E-ISSN 1095-9203, Vol. 365, no 6455, article id eaaw2619Article in journal (Refereed) Published
Abstract [en]

Malaria parasites adopt a remarkable variety of morphological life stages as they transition through multiple mammalian host and mosquito vector environments. We profiled the single-cell transcriptomes of thousands of individual parasites, deriving the first high-resolution transcriptional atlas of the entire Plasmodium berghei life cycle. We then used our atlas to precisely define developmental stages of single cells from three different human malaria parasite species, including parasites isolated directly from infected individuals. The Malaria Cell Atlas provides both a comprehensive view of gene usage in a eukaryotic parasite and an open-access reference dataset for the study of malaria parasites.

Place, publisher, year, edition, pages
American Association for the Advancement of Science, 2019
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-163672 (URN)10.1126/science.aaw2619 (DOI)000482464000044 ()31439762 (PubMedID)
Available from: 2019-10-21 Created: 2019-10-21 Last updated: 2019-10-21Bibliographically approved
Billker, O. (2018). CRISPRing the elephant in the room. Cell Host and Microbe, 24(6), 754-755
Open this publication in new window or tab >>CRISPRing the elephant in the room
2018 (English)In: Cell Host and Microbe, ISSN 1931-3128, E-ISSN 1934-6069, Vol. 24, no 6, p. 754-755Article in journal, Editorial material (Other academic) Published
Abstract [en]

The importance of guanylyl-cyclases (GCs) in apicomplexa has remained elusive due to the large size of the genes. Two recent studies, including Brown and Sibley, 2018 in this issue of Cell Host & Microbe, make elegant use of genome editing with CRISPR-Cas9 to characterize roles of GCs in Toxoplasma and Plasmodium.

Place, publisher, year, edition, pages
Elsevier, 2018
National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:umu:diva-154725 (URN)10.1016/j.chom.2018.11.015 (DOI)000453027400002 ()30543773 (PubMedID)2-s2.0-85057849741 (Scopus ID)
Available from: 2018-12-28 Created: 2018-12-28 Last updated: 2019-02-28Bibliographically approved
diva2:1260248
Open this publication in new window or tab >>Epistasis studies reveal redundancy among calcium-dependent protein kinases in motility and invasion of malaria parasites
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2018 (English)In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 9, article id 4248Article in journal (Refereed) Published
Abstract [en]

In malaria parasites, evolution of parasitism has been linked to functional optimisation. Despite this optimisation, most members of a calcium-dependent protein kinase (CDPK) family show genetic redundancy during erythrocytic proliferation. To identify relationships between phospho-signalling pathways, we here screen 294 genetic interactions among protein kinases in Plasmodium berghei. This reveals a synthetic negative interaction between a hypomorphic allele of the protein kinase G (PKG) and CDPK4 to control erythrocyte invasion which is conserved in P. falciparum. CDPK4 becomes critical when PKG-dependent calcium signals are attenuated to phosphorylate proteins important for the stability of the inner membrane complex, which serves as an anchor for the acto-myosin motor required for motility and invasion. Finally, we show that multiple kinases functionally complement CDPK4 during erythrocytic proliferation and transmission to the mosquito. This study reveals how CDPKs are wired within a stage-transcending signalling network to control motility and host cell invasion in malaria parasites.

Place, publisher, year, edition, pages
Nature Publishing Group, 2018
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:umu:diva-152977 (URN)10.1038/s41467-018-06733-w (DOI)000447123000024 ()30315162 (PubMedID)
Funder
EU, Horizon 2020, 695596
Available from: 2018-11-01 Created: 2018-11-01 Last updated: 2018-12-28Bibliographically approved
Kent, R. S., Modrzynska, K. K., Cameron, R., Philip, N., Billker, O. & Waters, A. P. (2018). Inducible developmental reprogramming redefines commitment to sexual development in the malaria parasite Plasmodium berghei. Nature Microbiology, 3(11), 1206-1213
Open this publication in new window or tab >>Inducible developmental reprogramming redefines commitment to sexual development in the malaria parasite Plasmodium berghei
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2018 (English)In: Nature Microbiology, E-ISSN 2058-5276, Vol. 3, no 11, p. 1206-1213Article in journal (Refereed) Published
Abstract [en]

During malaria infection, Plasmodium spp. parasites cyclically invade red blood cells and can follow two different developmental pathways. They can either replicate asexually to sustain the infection, or differentiate into gametocytes, the sexual stage that can be taken up by mosquitoes, ultimately leading to disease transmission. Despite its importance for malaria control, the process of gametocytogenesis remains poorly understood, partially due to the difficulty of generating high numbers of sexually committed parasites in laboratory conditions1. Recently, an apicomplexa-specific transcription factor (AP2-G) was identified as necessary for gametocyte production in multiple Plasmodium species2,3, and suggested to be an epigenetically regulated master switch that initiates gametocytogenesis4,5. Here we show that in a rodent malaria parasite, Plasmodium berghei, conditional overexpression of AP2-G can be used to synchronously convert the great majority of the population into fertile gametocytes. This discovery allowed us to redefine the time frame of sexual commitment, identify a number of putative AP2-G targets and chart the sequence of transcriptional changes through gametocyte development, including the observation that gender-specific transcription occurred within 6 h of induction. These data provide entry points for further detailed characterization of the key process required for malaria transmission.

Place, publisher, year, edition, pages
Nature Publishing Group, 2018
National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:umu:diva-154726 (URN)10.1038/s41564-018-0223-6 (DOI)000448229100007 ()30177743 (PubMedID)
Funder
Wellcome trust, 083811Wellcome trust, 107046
Available from: 2018-12-28 Created: 2018-12-28 Last updated: 2019-01-14Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0003-1716-168x

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