Discovery of Druggable Host Factors Critical to Plasmodium Liver-Stage Infection

Raphemot, Rene; Toro-Moreno, Maria; Lu, Kuan-Yi; Posfai, Dora; Derbyshire, Emily R.

doi:10.1016/j.chembiol.2019.05.011

Cited by 33 publications

(49 citation statements)

References 45 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We observed an enrichment of Golgi-derived vesicles near the parasite (Fig. 3A), consistent with other reports (De Niz et al, 2020;Raphemot et al, 2019). To assess Golgi morphology during infection, we infected HepG2-CD81 cells with P. yoelii sporozoites and stained cells with antibodies against the Golgi peripheral cytoplasmic membrane protein, GM130 (Golgi membrane protein of 130 kDa; golgin subfamily A member 2).…”

Section: Host Golgi and Golgi-derived Vesicles Interacts With Plasmodiumsupporting

confidence: 90%

“…Previous forward-genetic screens have partially provided that picture and identified host factors involved in Plasmodium infection (Prudencio et al, 2008;Raphemot et al, 2019;Rodrigues et al, 2008). However, these screens have exhibited very little overlap in identified factors (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…(coatomer subunit beta) and the ADP-ribosylation factor-binding protein GGA1 (Golgiassociated, gamma adaptin ear containing, ARF binding protein 1) as development factors (Raphemot et al, 2019) for Plasmodium LS infection. While these screens have provided valuable insights into parasite-host interactions, the range of targeted genes and overlap in the identified hits has been limited, suggesting that a complete complement of factors required for Plasmodium entry and development remains to be discovered.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

A genome-wide CRISPR-Cas9 screen identifies CENPJ as a host regulator of altered microtubule organization duringPlasmodiumliver infection

Vijayan

Arang

Wei³

et al. 2020

Preprint

View full text Add to dashboard Cite

SummaryPrior to initiating symptomatic malaria, Plasmodium parasites infect and develop within hepatocytes. We performed a forward genetic, genome-wide CRISPR-Cas9 screen to identify host regulators of Plasmodium liver infection. Single guide RNAs targeting genes involved in vesicle trafficking, cytoskeleton organization and lipid biogenesis altered Plasmodium liver development. We observed a redistribution of Golgi-derived vesicles and fragmented Golgi stacks with the parasitophorous vacuolar membrane (PVM). The host microtubule network and non-centrosomal microtubule organizing centers (ncMTOC) also re-localized following infection, closely associating with the parasite. Knocking out the centrosomal MTOC protein CENPJ exasperated the re-localization of MTOCs to the parasite and increased infection, suggesting that the parasite relies on ncMTOC assembly. Thus, we have uncovered a mechanism by which parasites sequester host material for survival and development. Our data provide a wealth of yet untested hypotheses about the elusive biology of the liver stage parasite and serves as a foundation for future investigation.

show abstract

Section: Host Golgi and Golgi-derived Vesicles Interacts With Plasmodiumsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

A genome-wide CRISPR-Cas9 screen identifies CENPJ as a host regulator of altered microtubule organization duringPlasmodiumliver infection

Vijayan

Arang

Wei³

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…Despite equally successful sporozoite invasion rates as in WT cells, parasites show poor survival, development, and ultimately relatively unsuccessful completion of the pre-erythrocytic cycle. Indeed, the downregulation of vesicular coat subunits (COPB2 and COPG1) in the COPI complex have also shown to impair Plasmodium development in the liver (Raphemot et al, 2019). Moreover, the β-COP subunit vesicles to also localize to the PVM in late schizonts.…”

Section: Discussionmentioning

confidence: 99%

Hijacking of the host cell Golgi byPlasmodiumliver stage parasites

Niz

Kaiser

Zuber

et al. 2020

Preprint

View full text Add to dashboard Cite

The intracellular lifestyle represents a challenge for the rapidly proliferating liver stage Plasmodium parasite. In order to scavenge host resources, Plasmodium has evolved the ability to target and manipulate host cell organelles. Using dynamic fluorescence-based imaging, we show a direct interplay between the pre-erythrocytic stages of Plasmodium berghei and the host cell Golgi during the entire liver stage development. Liver stage schizonts fragment the host cell Golgi into miniaturized stacks, which increases surface interactions with the parasite’s parasitophorous vacuole membrane. Interference with the host cell Golgi-linked vesicular machinery using specific dominant-negative Arf and Rab GTPases results in developmental arrest and diminished survival of liver stage parasites. Moreover, functional Rab11a is critical for the parasites ability to induce Golgi fragmentation. Altogether, we demonstrate that the structural and functional integrity of the host cell Golgi is necessary for optimal pre-erythrocytic development of P. berghei. The parasite hijacks the hepatocyte’s Golgi structure to optimize its own intracellular development.

show abstract

“…Arrayed CRISPR-Cas9 disruption libraries could theoretically help to identify human targets that are essential for parasite growth and development. In addition, a recent RNAi knockdown screen of the human druggable genome identified secretion factors as critical for parasite development in human liver cells [106].…”

Section: Discussionmentioning

confidence: 99%

Advances in omics-based methods to identify novel targets for malaria and other parasitic protozoan infections

Cowell

Winzeler

2019

Genome Med

View full text Add to dashboard Cite

A major advance in antimalarial drug discovery has been the shift towards cell-based phenotypic screening, with notable progress in the screening of compounds against the asexual blood stage, liver stage, and gametocytes. A primary method for drug target deconvolution in Plasmodium falciparum is in vitro evolution of compound-resistant parasites followed by whole-genome scans. Several of the most promising antimalarial drug targets, such as translation elongation factor 2 (eEF2) and phenylalanine tRNA synthetase (PheRS), have been identified or confirmed using this method. One drawback of this method is that if a mutated gene is uncharacterized, a substantial effort may be required to determine whether it is a drug target, a drug resistance gene, or if the mutation is merely a background mutation. Thus, the availability of high-throughput, functional genomic datasets can greatly assist with target deconvolution. Studies mapping genome-wide essentiality in P. falciparum or performing transcriptional profiling of the host and parasite during liver-stage infection with P. berghei have identified potentially druggable pathways. Advances in mapping the epigenomic regulation of the malaria parasite genome have also enabled the identification of key processes involved in parasite development. In addition, the examination of the host genome during infection has identified novel gene candidates associated with susceptibility to severe malaria. Here, we review recent studies that have used omics-based methods to identify novel targets for interventions against protozoan parasites, focusing on malaria, and we highlight the advantages and limitations of the approaches used. These approaches have also been extended to other protozoan pathogens, including Toxoplasma, Trypanosoma, and Leishmania spp., and these studies highlight how drug discovery efforts against these pathogens benefit from the utilization of diverse omics-based methods to identify promising drug targets.

show abstract

Discovery of Druggable Host Factors Critical to Plasmodium Liver-Stage Infection

Cited by 33 publications

References 45 publications

A genome-wide CRISPR-Cas9 screen identifies CENPJ as a host regulator of altered microtubule organization duringPlasmodiumliver infection

A genome-wide CRISPR-Cas9 screen identifies CENPJ as a host regulator of altered microtubule organization duringPlasmodiumliver infection

Hijacking of the host cell Golgi byPlasmodiumliver stage parasites

Advances in omics-based methods to identify novel targets for malaria and other parasitic protozoan infections

Contact Info

Product

Resources

About