Malaria artemisinin resistance: an extracellular vesicles export hypothesis

Tandoh, Kwesi Z; Morang’a, Collins M.; Wilson, Michael D.; Quashie, Neils B; Duah-Quashie, Nancy Odurowah

doi:10.1016/j.pt.2022.05.004

Cited by 5 publications

(6 citation statements)

References 14 publications

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“…That the module containing such a gene was found to be upregulated under DHA pressure in ARTr suggests a role for EVs in ARTr. We opine that such a role for EVs in ARTr is likely hinged on the increased tolerance to oxidative stress arm of evidence explaining the molecular mechanisms of ARTr (Tandoh et al, 2022). Within this framework, we suggest that EVs may act as vehicles mediating the active removal of built-up and accumulating proteotoxic waste of ART action.…”

Section: Discussionmentioning

confidence: 88%

“…We posited a molecular mechanistic model of ART resistance involving EVs as vehicles responsible for the active removal of ART induced proteotoxic waste from the P. falciparum-infected erythrocyte (Tandoh et al, 2022). To test this model, we designed a targeted transcriptome exploratory analysis of two ARTr and one ART sensitive parasites (with three replicates each) under the three conditions: untreated, 0.1% DMSO treated and 700nM DHA treated for six hours.…”

Section: Discussionmentioning

confidence: 99%

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Transcriptome-module phenotype association study implicates extracellular vesicles biogenesis in Plasmodium falciparum artemisinin resistance

Tandoh

Hagan

Wilson

et al. 2022

Front. Cell. Infect. Microbiol.

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Plasmodium falciparum malaria is still an important disease in sub-Saharan Africa (sSA). Great strides have been made in its control spear-headed by artemisinin (ART)-based combination therapies (ACTs). However, concerns about the imminent spread of ART-resistant (ARTr) malaria parasites to sSA threaten gains already made. Attempts to mitigate this risk have highlighted the need to discover novel P. falciparum drug targets. Therefore, studies to deepen our understanding of the biology of P. falciparum are needed. The role of extracellular vesicles (EVs) in the biology of malaria parasites is not fully understood. Recently, the ART resistance-associated transcriptional profile has been reported to involve several biological processes connected to vesicular trafficking, proteotoxic stress, erythrocyte remodelling, and mitochondrial metabolism. We explored a role for EVs in developing the P. falciparum ARTr phenotype using bulk RNA sequencing of unsynchronized parasite cultures under untreated, 0.1% dimethyl sulfoxide and 700nM dihydroartemisinin treated conditions for six hours. As pathway and gene ontology analysis is limited in its curated knowledge repertoire on EVs biogenesis in P. falciparum, we used a modular (gene set) analysis approach to explore whether an EVs biogenesis module is associated with the ARTr phenotype in P. falciparum. We first generated well-defined EVs modules of interest and used statistical tools to determine differences in their expression among the parasite and treatment conditions. Then we used gene set enrichment analysis to determine the strength of the association between each EVs module of interest and the ARTr phenotype. This transcriptome-module phenotype association study (TMPAS) represents a well-powered approach to making meaningful discoveries out of bulk gene expression data. We identified four EVs module of interest and report that one module representing gene sets with correlated expression to PF3D7_1441800 – involved with EVs biogenesis in P. falciparum - is associated with the ARTr phenotype (R539T_DHA_treated versus R539T_untreated: normalized enrichment score (NES) = 1.1830174, FDR q-value < 0.25; C580R_DHA_treated versus C580R_untreated: NES = 1.2457103, FDR q-value < 0.25). PF3D7_1441800 has been reported to reduce EVs production when knocked out in P. falciparum. Altogether, our findings suggest a role for EVs in developing ART resistance and warrant further studies interrogating this association.

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Section: Discussionmentioning

confidence: 88%

Section: Discussionmentioning

confidence: 99%

Transcriptome-module phenotype association study implicates extracellular vesicles biogenesis in Plasmodium falciparum artemisinin resistance

Tandoh

Hagan

Wilson

et al. 2022

Front. Cell. Infect. Microbiol.

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“…Another interesting area evolving under the umbrella of ART resistance in P. falciparum is whether parasite-parasite communication is the only framework for EV roles in drug resistance. This breakout idea has been proposed as a new enquiry and is described as an EV export hypothesis for P. falciparum ART resistance development [14]. It is interesting that a similar EV export motif has recently been suggested as the mechanism employed by the parasite to regulate intracellular RNA levels [20].…”

Section: Is Extracellular Vesicle Biogenesis a New Druggable Space?mentioning

confidence: 99%

“…The impact of this line of interrogation could yield the drug solutions needed presently to mitigate the inevitable risk of the emergence of ACT drug resistance in malaria parasites. [14] A conceptual argument implicating EVs in the development of ART resistance in malaria parasites outside the extant parasite-parasite communication theme. The authors introduce the EV export hypothesis, which states that EVs act as the vehicles involved in actively maintaining parasite cellular homeostasis in the face of ART-induced oxidative stress thus driving the ART resistance phenotype.…”

Section: Study/publication Key Findingmentioning

confidence: 99%

Extracellular Vesicles: Translational Agenda Questions for Three Protozoan Parasites

Tandoh,

Ibarra‐Meneses,

Langlais

et al. 2024

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The protozoan parasites Plasmodium falciparum, Leishmania spp. and Trypanosoma cruzi continue to exert a significant toll on the disease landscape of the human population in sub‐Saharan Africa and Latin America. Control measures have helped reduce the burden of their respective diseases—malaria, leishmaniasis and Chagas disease—in endemic regions. However, the need for new drugs, innovative vaccination strategies and molecular markers of disease severity and outcomes has emerged because of developing antimicrobial drug resistance, comparatively inadequate or absent vaccines, and a lack of trustworthy markers of morbid outcomes. Extracellular vesicles (EVs) have been widely reported to play a role in the biology and pathogenicity of P. falciparum, Leishmania spp. and T. cruzi ever since they were discovered. EVs are secreted by a yet to be fully understood mechanism in protozoans into the extracellular milieu and carry a cargo of diverse molecules that reflect the originator cell's metabolic state. Although our understanding of the biogenesis and function of EVs continues to deepen, the question of how EVs in P. falciparum, Leishmania spp. and T. cruzi can serve as targets for a translational agenda into clinical and public health interventions is yet to be fully explored. Here, as a consortium of protozoan researchers, we outline a plan for future researchers and pose three questions to direct an EV's translational agenda in P. falciparum, Leishmania spp. and T. cruzi. We opine that in the long term, executing this blueprint will help bridge the current unmet needs of these medically important protozoan diseases in sub‐Saharan Africa and Latin America.

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“…Similar problems also exist in malaria control. The emergence and spread of drug resistant isolates have posed enormous challenges in the treatment of human malaria [8][9][10][11]. In contrast, the RTS, S vaccine recommended by the World Health Organization has low efficacy, particularly in infants, who are highly susceptible to malaria [12].…”

Section: Introductionmentioning

confidence: 99%

Genetic Manipulation Toolkits in Apicomplexan Parasites

et al. 2022

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Apicomplexan parasites are a group of intracellular pathogens of great medical and veterinary importance, including Toxoplasma gondii and Plasmodium, which cause toxoplasmosis and malaria, respectively. Efficient and accurate manipulation of their genomes is essential to dissect their complex biology and to design new interventions. Over the past several decades, scientists have continually optimized the methods for genetic engineering in these organisms, and tremendous progress has been made. Here, we review the genetic manipulation tools currently used in several apicomplexan parasites, and discuss their advantages and limitations. The widely used CRISPR/Cas9 genome editing technique has been adapted in several apicomplexans and shown promising efficiency. In contrast, conditional gene regulation is available in only a limited number of organisms, mainly Plasmodium and Toxoplasma, thus posing a research bottleneck for other parasites. Conditional gene regulation can be achieved with tools that regulate gene expression at the DNA, RNA or protein level. However, a universal tool to address all needs of conditional gene manipulation remains lacking. Understanding the scope of application is key to selecting the proper method for gene manipulation.

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Malaria artemisinin resistance: an extracellular vesicles export hypothesis

Cited by 5 publications

References 14 publications

Transcriptome-module phenotype association study implicates extracellular vesicles biogenesis in Plasmodium falciparum artemisinin resistance

Transcriptome-module phenotype association study implicates extracellular vesicles biogenesis in Plasmodium falciparum artemisinin resistance

Extracellular Vesicles: Translational Agenda Questions for Three Protozoan Parasites

Genetic Manipulation Toolkits in Apicomplexan Parasites

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