Gene-by-gene screen of the unknown proteins encoded on Plasmodium falciparum chromosome 3

Kimmel, Jessica; Schmitt, Marius; Sinner, Alexej; Jansen, Pascal W.; Mainye, Sheila; Ramón-Zamorano, Gala; Toenhake, Christa Geeke; Wichers, Jan Stephan; Cronshagen, Jakob; Sabitzki, Ricarda; Mesén-Ramírez, Paolo; Behrens, Hannah Michaela; Bártfai, Richárd; Spielmann, Tobias

doi:10.1016/j.cels.2022.12.001

Cited by 18 publications

(19 citation statements)

References 64 publications

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“…Nuclei were stained with 1 μg/mL Hoechst 33342 (Invitrogen). Microtubules were visualized by incubation of parasites in medium containing 1:1,000 TubulinTracker deep red (Thermo Fisher Scientific; dissolved in dimethyl sulfoxide [DMSO]), which labels polymerized tubulin, for 15 min at 37°C prior to imaging, as previously described ( 94 ). Images were processed using Fiji ( 91 ), and Adobe Photoshop CC 2021 was used for display purposes only.…”

Section: Methodsmentioning

confidence: 99%

A Microtubule-Associated Protein Is Essential for Malaria Parasite Transmission

Wichers

Binder

Mesén-Ramírez

et al. 2023

mBio

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A key structural feature driving the transition between different life cycle stages of the malaria parasite is the unique three-membrane pellicle, consisting of the parasite plasma membrane (PPM) and a double membrane structure underlying the PPM termed the inner membrane complex (IMC). Additionally, there are numerous linearly arranged intramembranous particles (IMPs) linked to the IMC, which likely link the IMC to the subpellicular microtubule cytoskeleton.

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Section: Methodsmentioning

confidence: 99%

A Microtubule-Associated Protein Is Essential for Malaria Parasite Transmission

Wichers

Binder

Mesén-Ramírez

et al. 2023

mBio

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“…Efforts to knockout or knockdown NDC80 and Nuf2 in P. berghei were not successful, consistent with these genes being essential 19,24 . Similarly, knock sideways and promoter swap methods in P. falciparum and P. yoelii confirm that NDC80 plays an essential role in replication 25,26,27 .…”

Section: Introductionmentioning

confidence: 77%

Plasmodium falciparum kinetochore proteins stabilise a nexus between the mitotic apparatus and the apical complex

Tilley,

Li,

Shami

et al. 2023

Preprint

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Plasmodium falciparum is the causative agent of malaria and remains a pathogen of global importance. Asexual blood stage replication, via a process called schizogony, is an important target for the development of new antimalarials. Here we used Airyscan super resolution imaging coupled with ultrastructure-expansion microscopy to probe the organization and function of the chromosome-capturing kinetochores in relation to the mitotic spindle, the centriolar plaque and the apical organelles during schizont development. We provide evidence that the inner and outer domains of the centriolar plaque nucleate the spindle and cytoplasmic microtubules, respectively. This, in turn, provides a physical nexus between the mitotic apparatus and the apical complex. Conditional disruption of the kinetochore components, PfNDC80 and PfNuf2, causes aberrant mitotic spindle assembly and disrupted karyokinesis. Surprisingly, kinetochore disruption also leads to disengagement of the centrin-containing, outer centriolar plaque from the nuclear envelope. Severing the connection between the nucleus and the apical complex leads to the formation of merozoites lacking nuclei. The data suggest that correct assembly of the kinetochore/ spindle complex plays a previously unrecognised a role in positioning the nascent apical complex in developing P. falciparum merozoites.

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“…Finally, the human-infecting zoonotic P. knowlesi parasite could also be tested for slow growth as an intermediate pre-clinical model 51,52 as it can be cultured in vitro like P. falciparum but shows a higher transfection efficacy and a fast red blood stage cycle of just 24 hours 53 . Lastly, slow growing P. falciparum parasites were recently also identified by a screen using selection linked resistance marker integration, which could help to prescreen for gene-deletions resulting in an avirulent phenotype 54 .…”

Section: Discussionmentioning

confidence: 99%

Vaccination by single dose sporozoite injection of blood stage attenuated malaria parasites

Sattler,

Keiber,

Abdelrahim

et al. 2023

Preprint

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An efficient malaria vaccine remains elusive. As an alternative to malaria subunit vaccines, vaccination approaches are currently explored using live Plasmodium parasites, either attenuated mosquito-derived sporozoites or attenuated blood stage parasites. Both approaches would profit from the availability of attenuated and avirulent parasites with a reduced blood stage multiplication rate. Ideally, such slow growing parasites would proceed normally through the mosquito but cause a self-limiting infection upon transmission. Here we screened gene-deletion mutants of the rodent parasite P. berghei and the human parasite P. falciparum for slow growth. In addition, we tested the P. berghei mutants for avirulence in mice and self-resolving blood stage infections, while preserving sporozoite formation and liver infection. Targeting fifty genes yielded seventeen P. berghei gene-deletion mutants with two mutants causing self-clearing infections in mice while retaining full transmissibility through mosquitoes. For those, infection of mice by a low number of blood stages, infected-mosquito bites or by single injection of sporozoites led to protection from disease after challenge with wild type sporozoites. Two of six generated P. falciparum gene-deletion mutants showed a slow growth rate. Slow growing, avirulent P. falciparum mutants will constitute valuable tools to inform on the induction of immune responses and aid in developing new as well as safeguarding existing attenuated parasite vaccines.

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Gene-by-gene screen of the unknown proteins encoded on Plasmodium falciparum chromosome 3

Cited by 18 publications

References 64 publications

A Microtubule-Associated Protein Is Essential for Malaria Parasite Transmission

A Microtubule-Associated Protein Is Essential for Malaria Parasite Transmission

Plasmodium falciparum kinetochore proteins stabilise a nexus between the mitotic apparatus and the apical complex

Vaccination by single dose sporozoite injection of blood stage attenuated malaria parasites

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