Analysis of erythrocyte signalling pathways during Plasmodium falciparum infection identifies targets for host-directed antimalarial intervention

Adderley, Jack; Freyend, Simona John von; Jackson, Sarah; Bird, Megan J.; Burns, Amy L.; Anar, Burçu; Metcalf, Tom; Semblat, Jean-Philippe; Billker, Oliver; Wilson, Danny W.; Doerig, Christian

doi:10.1038/s41467-020-17829-7

Cited by 33 publications

(67 citation statements)

References 74 publications

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“…Recently, Adderley et al . (2020) demonstrated the feasibility of targeting the host’s erythrocyte signaling pathways as an antiplasmodial strategy [ 52 ]. While this specific mechanism does not seem to be present in the DLAe material, a variety of possible mechanisms have been proposed.…”

Section: Discussionmentioning

confidence: 99%

“…The discrepancy between in-vitro and in-vivo activities of the plant material suggests that there is an important interaction between the host and the DLA that potentiates therapeutic activity. Recently, Adderley et al (2020) demonstrated the feasibility of targeting the host's erythrocyte signaling pathways as an antiplasmodial strategy [52]. While this specific mechanism does not seem to be present in the DLAe material, a variety of possible mechanisms have been proposed.…”

Section: Plos Onementioning

confidence: 99%

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In vitro analyses of Artemisia extracts on Plasmodium falciparum suggest a complex antimalarial effect

Gruessner

Weathers

2021

PLoS ONE

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Dried-leaf Artemisia annua L. (DLA) antimalarial therapy was shown effective in prior animal and human studies, but little is known about its mechanism of action. Here IC50s and ring-stage assays (RSAs) were used to compare extracts of A. annua (DLAe) to artemisinin (ART) and its derivatives in their ability to inhibit and kill Plasmodium falciparum strains 3D7, MRA1252, MRA1240, Cam3.11 and Cam3.11rev in vitro. Strains were sorbitol and Percoll synchronized to enrich for ring-stage parasites that were treated with hot water, methanol and dichloromethane extracts of DLA, artemisinin, CoArtem™, and dihydroartemisinin. Extracts of A. afra SEN were also tested. There was a correlation between ART concentration and inhibition of parasite growth. Although at 6 hr drug incubation, the RSAs for Cam3.11rev showed DLA and ART were less effective than high dose CoArtem™, 8 and 24 hr incubations yielded equivalent antiparasitic results. For Cam3.11, drug incubation time had no effect. DLAe was more effective on resistant MRA-1240 than on the sensitive MRA-1252 strain. Because results were not as robust as observed in animal and human studies, a host interaction was suspected, so sera collected from adult and pediatric Kenyan malaria patients was used in RSA inhibition experiments and compared to sera from adults naïve to the disease. The sera from both age groups of malaria patients inhibited parasite growth ≥ 70% after treatment with DLAe and compared to malaria naïve subjects suggesting some host interaction with DLA. The discrepancy between these data and in-vivo reports suggested that DLA’s effects require an interaction with the host to unlock their potential as an antimalarial therapy. Although we showed there are serum-based host effects that can kill up to 95% of parasites in vitro, it remains unclear how or if they play a role in vivo. These results further our understanding of how DLAe works against the malaria parasite in vitro.

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Section: Discussionmentioning

confidence: 99%

Section: Plos Onementioning

confidence: 99%

In vitro analyses of Artemisia extracts on Plasmodium falciparum suggest a complex antimalarial effect

Gruessner

Weathers

2021

PLoS ONE

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“…falciparum life cycle, and that its inhibition terminates the life cycle by preventing merozoite egress from the infected RBC. Data supporting this contention include the observations that i) band 3 tyrosine phosphorylation dramatically increases as parasite maturation progresses [ 23 , 24 , 37 ], ii) Syk is the major erythrocyte tyrosine kinase found to phosphorylate band 3 in vivo [ 21 , 51 ], iii) Syk is progressively activated and recruited to the RBC membrane as the parasite matures [ 23 , 52 , 53 ], iv) all known Syk inhibitors (and band 3 tyrosine phosphorylation inhibitors) display antimalarial activity [ 24 , 37 ], and v) incubation of parasite cultures with Syk inhibitors does not significantly alter earlier stages of parasite maturation even though the rise in band 3 tyrosine phosphorylation begins early and increases as the parasite progresses through its life cycle [ 24 , 37 ]. Collectively, these results argue that Syk kinase inhibitors interrupt a critical step required for parasite escape from its RBC host.…”

Section: Discussionmentioning

confidence: 99%

Identification of tyrosine kinase inhibitors that halt Plasmodium falciparum parasitemia

et al. 2020

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Although current malaria therapies inhibit pathways encoded in the parasite’s genome, we have looked for anti-malaria drugs that can target an erythrocyte component because development of drug resistance might be suppressed if the parasite cannot mutate the drug’s target. In search for such erythrocyte targets, we noted that human erythrocytes express tyrosine kinases, whereas the Plasmodium falciparum genome encodes no obvious tyrosine kinases. We therefore screened a library of tyrosine kinase inhibitors from Eli Lilly and Co. in a search for inhibitors with possible antimalarial activity. We report that although most tyrosine kinase inhibitors exerted no effect on parasite survival, a subset of tyrosine kinase inhibitors displayed potent anti-malarial activity. Moreover, all inhibitors found to block tyrosine phosphorylation of band 3 specifically suppressed P. falciparum survival at the parasite egress stage of its intra-erythrocyte life cycle. Conversely, tyrosine kinase inhibitors that failed to block band 3 tyrosine phosphorylation but still terminated the parasitemia were observed to halt parasite proliferation at other stages of the parasite’s life cycle. Taken together these results suggest that certain erythrocyte tyrosine kinases may be important to P. falciparum maturation and that inhibitors that block these kinases may contribute to novel therapies for P. falciparum malaria.

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“…This positions the antibody microarray as an ideal system to assess the signalling environment inside human cells in disease and infection settings. We have applied microarrays in our efforts to understand how intracellular pathogens alter their host cells during development and identified a number of key host proteins essential to the proliferation of various pathogens 10-12 . However, the datasets obtained from antibody microarray experiments are quite complex and ultimately difficult to interpret holistically.…”

Section: Introductionmentioning

confidence: 99%

“…The network analysis strategy designed here was formulated using PhosphoAtlas 8 as a framework, which was adapted to includes the effect of the phosphorylation interactions and curated to include connections provided by the microarray developer (Kinexus). To develop a random walks-based function, we used the published datasets on the blood-stage develop of the human malaria parasite, Plasmodium falciparum 10 . This consisted of; a control dataset (uninfected red blood cells) and three parasite-infected datasets which coincide with the major distinguishable stages of parasite development (see published work for more detail 10 ).…”

Section: Introductionmentioning

confidence: 99%

Network analysis of large phospho-signalling datasets: application to Plasmodium-erythrocyte interactions

Adderley

O'Donoghue

Doerig

et al. 2021

Preprint

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Phosphorylation based signalling is a complicated and intertwined series of pathways critical to all domains of life. This interconnectivity, though essential to life, makes understanding and decoding the interactions difficult. Large datasets of phosphorylation interactions through the activity of kinases on their numerous effectors are now being generated, however interpretation of the network environment remains challenging. In humans, many phosphorylation interactions have been identified across published works to form the known phosphorylation interaction network. We overlayed phosphorylation datasets onto this network which provided information to each of the connections. To analyse the datasets now mapped into a network, we designed a pathway analysis that uses random walks to identify chains of phosphorylation events occurring much more or much less frequently than expected. This analysis highlights pathways of phosphorylation that work synergistically, providing a rapid interpretation of the most critical pathways in a given dataset. Here we used datasets of human red blood cells infected with the notable stages of Plasmodium falciparum asexual development. The analysis identified several known signalling interactions, and additional interactions which could form the basis of numerous future studies. The network analysis designed here is widely applicable to any comparative phosphorylation dataset across infection and disease and can provide a rapid and reliable analysis to guide validation studies.

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Analysis of erythrocyte signalling pathways during Plasmodium falciparum infection identifies targets for host-directed antimalarial intervention

Cited by 33 publications

References 74 publications

In vitro analyses of Artemisia extracts on Plasmodium falciparum suggest a complex antimalarial effect

In vitro analyses of Artemisia extracts on Plasmodium falciparum suggest a complex antimalarial effect

Identification of tyrosine kinase inhibitors that halt Plasmodium falciparum parasitemia

Network analysis of large phospho-signalling datasets: application to Plasmodium-erythrocyte interactions

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