Uncovering the essential genes of the human malaria parasite
            <i>Plasmodium falciparum</i>
            by saturation mutagenesis

Zhang, Min; Wang, Chengqi; Otto, Thomas D.; Oberstaller, Jenna; Liao, Xiangyun; Adapa, Swamy Rakesh; Udenze, Kenneth O.; Bronner, Iraad F.; Casandra, Deborah; Mayho, Matthew; Brown, J. Y.; Li, Suzanne; Swanson, Justin; Rayner, Julian C.; Jiang, Rays H. Y.; Adams, John

doi:10.1126/science.aap7847

Cited by 701 publications

(844 citation statements)

References 41 publications

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“…However, there were some discrepancies between their global mutagenesis insertion analysis and our targeted approach. Zhang et al , () suggested that FIKK5 is essential, however we were able to delete FIKK5 from the parasites’ genome. This type of discrepancy to large‐scale studies is not uncommon and highlights the need for detailed and specific characterisation to confirm essentiality through a more targeted approach.…”

Section: Discussionmentioning

confidence: 73%

“…This type of discrepancy to large‐scale studies is not uncommon and highlights the need for detailed and specific characterisation to confirm essentiality through a more targeted approach. Additionally, this study implied that FIKK10.2 is dispensable, and FIKK10.1 and FIKK9.1 have a low mutagenesis score, suggesting that disruption of these two FIKKs significantly affected parasite fitness (Zhang et al , ). It does remain possible that the global approach is able to detect alterations that partially disrupt but do not delete genes resulting in truncated or disrupted protein expression or function.…”

Section: Discussionmentioning

confidence: 89%

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Identification of essential exported Plasmodium falciparum protein kinases in malaria‐infected red blood cells

2019

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Summary FIKK kinases in the human malaria parasite Plasmodium falciparum are attractive targets for new anti‐malaria drugs, as they have no orthologues in humans and have been linked to disease severity. Six FIKKs are known to be exported into red blood cells (RBCs) where they mediate dramatic structural and functional changes to RBCs that are central to pathogenesis. Eleven members of this family, which are predicted to be exported into infected RBCs (iRBCs), remain uncharacterised. Using a targeted gene‐knockout approach, we have characterised these FIKKs and discovered that five are essential for parasite survival. Three of these five FIKKs (FIKK9.1, FIKK10.1, FIKK10.2) were exported from the parasite into iRBCs and for two of these (FIKK9.1 and FIKK10.1), export was via Maurer’s clefts (parasite‐derived structures involved in protein trafficking and pathognomonic of falciparum malaria). Of the remaining two essential kinases, FIKK3 was associated with rhoptries (specialised protein secretory organelles in the parasite) and FIKK9.5 was localised in the parasite nucleus. The diverse localisation and essentiality of these FIKKs demonstrate that they play different but essential roles in the survival of P. falciparum in RBCs and therefore are attractive new drug targets for the prevention or treatment of falciparum malaria.

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Section: Discussionmentioning

confidence: 73%

Section: Discussionmentioning

confidence: 89%

Identification of essential exported Plasmodium falciparum protein kinases in malaria‐infected red blood cells

2019

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“…Our findings on the essentiality of SPATR in P. berghei blood stage are supported by the binding of HABPs to human RBCs (Curtidor et al, ). However, Piggyback screen performed in P. falciparum indicates that SPATR is dispensable in blood stage (Zhang et al, ). There are, however, important differences in the way P. berghei and P. falciparum behave as P. falciparum is known to have redundancy in pathways for invading erythrocytes.…”

Section: Discussionmentioning

confidence: 99%

Secreted protein with altered thrombospondin repeat (SPATR) is essential for asexual blood stages but not required for hepatocyte invasion by the malaria parasite Plasmodium berghei

Gupta

Mishra

Choudhary

et al. 2019

Molecular Microbiology

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Upon entering its mammalian host, the malaria parasite productively invades two distinct cell types, that is, hepatocytes and erythrocytes during which several adhesins/invasins are thought to be involved. Many surface‐located proteins containing thrombospondin Type I repeat (TSR) which help establish host–parasite molecular crosstalk have been shown to be essential for mammalian infection. Previous reports indicated that antibodies produced against Plasmodium falciparum secreted protein with altered thrombospondin repeat (SPATR) block hepatocyte invasion by sporozoites but no genetic evidence of its contribution to invasion has been reported. After failing to generate Spatr knockout in Plasmodium berghei blood stages, a conditional mutagenesis system was employed. Here, we show that SPATR plays an essential role during parasite's blood stages. Mutant salivary gland sporozoites exhibit normal motility, hepatocyte invasion, liver stage development and rupture of the parasitophorous vacuole membrane resulting in merosome formation. But these mutant hepatic merozoites failed to establish a blood stage infection in vivo. We provide direct evidence that SPATR is not required for hepatocyte invasion but plays an essential role during the blood stages of P. berghei.

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“…This is in accord with recent data that suggest the products of glycolysis (both pre‐ and post‐mitochondrial) are used in biosynthesis in the malarial parasite (Ke et al, ). In another recent study (Zhang et al, ), mutagenic index scores (MISs) calculations have predicted Pf MDH as an essential enzyme. In contrast, the PIA experiments revealed no effect on the proliferation of MDH mutant overexpressing parasites.…”

Section: Discussionmentioning

confidence: 99%

Oligomeric protein interference validates druggability of aspartate interconversion in Plasmodium falciparum

et al. 2019

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The appearance of multi‐drug resistant strains of malaria poses a major challenge to human health and validated drug targets are urgently required. To define a protein's function in vivo and thereby validate it as a drug target, highly specific tools are required that modify protein function with minimal cross‐reactivity. While modern genetic approaches often offer the desired level of target specificity, applying these techniques is frequently challenging—particularly in the most dangerous malaria parasite, Plasmodium falciparum . Our hypothesis is that such challenges can be addressed by incorporating mutant proteins within oligomeric protein complexes of the target organism in vivo. In this manuscript, we provide data to support our hypothesis by demonstrating that recombinant expression of mutant proteins within P. falciparum leverages the native protein oligomeric state to influence protein function in vivo, thereby providing a rapid validation of potential drug targets. Our data show that interference with aspartate metabolism in vivo leads to a significant hindrance in parasite survival and strongly suggest that enzymes integral to aspartate metabolism are promising targets for the discovery of novel antimalarials.

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Uncovering the essential genes of the human malaria parasite Plasmodium falciparum by saturation mutagenesis

Cited by 701 publications

References 41 publications

Identification of essential exported Plasmodium falciparum protein kinases in malaria‐infected red blood cells

Identification of essential exported Plasmodium falciparum protein kinases in malaria‐infected red blood cells

Secreted protein with altered thrombospondin repeat (SPATR) is essential for asexual blood stages but not required for hepatocyte invasion by the malaria parasite Plasmodium berghei

Oligomeric protein interference validates druggability of aspartate interconversion in Plasmodium falciparum

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