A heat-shock response regulated by the PfAP2-HS transcription factor protects human malaria parasites from febrile temperatures

Tintó-Font, Elisabet; Michel-Todó, Lucas; Russell, Timothy J.; Casas-Vila, Núria; Conway, David J.; Bozdech, Zbynek; Llinás, Manuel; Cortés, Alfred

doi:10.1038/s41564-021-00940-w

Cited by 42 publications

(54 citation statements)

References 70 publications

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“…This study identified some functional RNA structural elements, demonstrated that a dynamic RNA structurome responds to two different temperatures, and identified novel RNA thermometers. Our study adds to the accumulating evidence that febrile temperatures can suppress the growth and development of parasites with a maximal effect on trophozoites ( Tinto-Font et al, 2021 ). We identified a global trend of significantly reduced average icSHAPE scores for entire transcripts at 26°C compared with those at 37°C in the trophozoite stage based on the icSHAPE in vivo , as well as icSHAPE in vitro .…”

Section: Discussionmentioning

confidence: 53%

RNA Secondary Structurome Revealed Distinct Thermoregulation in Plasmodium falciparum

Zhang

et al. 2022

Front. Cell Dev. Biol.

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The development of Plasmodium parasites, a causative agent of malaria, requests two hosts and the completion of 11 different parasite stages during development. Therefore, an efficient and fast response of parasites to various complex environmental changes, such as ambient temperature, pH, ions, and nutrients, is essential for parasite development and survival. Among many of these environmental changes, temperature is a decisive factor for parasite development and pathogenesis, including the thermoregulation of rRNA expression, gametogenesis, and parasite sequestration in cerebral malaria. However, the exact mechanism of how Plasmodium parasites rapidly respond and adapt to temperature change remains elusive. As a fundamental and pervasive regulator of gene expression, RNA structure can be a specific mechanism for fine tuning various biological processes. For example, dynamic and temperature-dependent changes in RNA secondary structures can control the expression of different gene programs, as shown by RNA thermometers. In this study, we applied the in vitro and in vivo transcriptomic-wide secondary structurome approach icSHAPE to measure parasite RNA structure changes with temperature alteration at single-nucleotide resolution for ring and trophozoite stage parasites. Among 3,000 probed structures at different temperatures, our data showed structural changes in the global transcriptome, such as S-type rRNA, HRPII gene, and the erythrocyte membrane protein family. When the temperature drops from 37°C to 26°C, most of the genes in the trophozoite stage cause significantly more changes to the RNA structure than the genes in the ring stage. A multi-omics analysis of transcriptome data from RNA-seq and RNA structure data from icSHAPE reveals that the specific RNA secondary structure plays a significant role in the regulation of transcript expression for parasites in response to temperature changes. In addition, we identified several RNA thermometers (RNATs) that responded quickly to temperature changes. The possible thermo-responsive RNAs in Plasmodium falciparum were further mapped. To this end, we identified dynamic and temperature-dependent RNA structural changes in the P. falciparum transcriptome and performed a comprehensive characterization of RNA secondary structures over the course of temperature stress in blood stage development. These findings not only contribute to a better understanding of the function of the RNA secondary structure but may also provide novel targets for efficient vaccines or drugs.

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Section: Discussionmentioning

confidence: 53%

RNA Secondary Structurome Revealed Distinct Thermoregulation in Plasmodium falciparum

Zhang

et al. 2022

Front. Cell Dev. Biol.

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“…The immediate stress response (cluster 2, Fig. 2e top panel) includes Hsp70-1, which has been previously shown to be transcriptionally induced in response to amino acid starvation (Pavlovic Djuranovic et al, 2020) and to be induced by the ApiAP2 transcription factor PfAP2-HS (PF3D7_1342900) after heat shock (Tintó-Font et al, 2021), suggesting it may be a central early stress response gene in the Plasmodium ISR downstream of various stimuli. Several other chaperones as well as the drug efflux pump MDR1 were also induced.…”

Section: Discussionmentioning

confidence: 99%

PfD123 modulates K13-mediated survival and recovery after artemisinin exposure

Nötzel

Kafsack

2022

Preprint

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Recent advances in curbing the deadly toll of malaria have been threatened by the emergence of parasites resistant to the front-line antimalarial artemisinin. Resistance is mediated by point-mutations in the parasite protein Kelch13, but the mechanism of resistance is multi-factorial and only partially understood. Resistance-conferring Kelch13 mutations have been shown to lead to low-level activation of the parasite's integrated stress response (ISR) which has a protective effect against artemisinin through an unclear mechanism. Furthermore, only a subpopulation of resistant parasites ever survives drug exposure, implying an underlying heterogeneity. By applying scRNAseq to the resistance-relevant early ring stage, we found expansion of a subpopulation in Kelch13 mutant parasites that is chiefly characterized by transcription of the putative positive translational regulator D123, while we conversely observed reduced D123 protein levels at the same stage. Analogous inverse changes in D123 expression are produced by experimental activation of the ISR, and genetically manipulating D123 expression modulates sensitivity to artemisinin, establishing it as a stress-responsive gene that contributes to artemisinin resistance in Kelch13-mutant malaria parasites.

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“…Over half of the ApiAP2 proteins are predicted to be essential for the IDC in P. falciparum (15–17). In-depth studies of ApiAP2 proteins to date have demonstrated roles in transcriptional activation or repression affecting diverse processes including invasion(18, 19), heterochromatin maintenance(17, 20–23), sexual and mosquito stage differentiation(16, 24–34), and heat stress tolerance(35). Despite these properties which make ApiAP2 proteins potential drug targets, no efforts to date have focused on targeting the sequence specific DNA binding ApiAP2 transcription factors.…”

Section: Introductionmentioning

confidence: 99%

Identification of Antimalarial Compounds that Inhibit Apicomplexan AP2 Proteins

Russell

Silva

Crowley

et al. 2022

Preprint

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Plasmodium parasites are reliant on the Apicomplexan AP2 (ApiAP2) transcription factor family to regulate gene expression programs. The AP2 DNA binding domains have no homology to the human or mosquito hosts, making them potential drug targets. Using an in-silico screen to dock thousands of small molecules into the crystal structure of the AP2-EXP (Pf3D7_1466400) AP2 domain (PDB:3IGM), we identified compounds that interact with this domain. Four compounds were found to compete for DNA binding with AP2-EXP and at least one additional ApiAP2 protein. Our top ApiAP2 competitor compound perturbs the transcriptome of P. falciparum trophozoites and results in a decrease in abundance of log2 fold change > 2 for 50% (46/93) of AP2-EXP target genes identified. Additionally, two ApiAP2 competitor compounds have anti- Plasmodium activity against P. berghei mosquito stage parasites. In summary, we describe a novel set of antimalarial compounds that are targeted against the ApiAP2 family of proteins. These compounds may be used for future chemical genetic interrogation of ApiAP2 proteins or serve as starting points for a new class of antimalarial therapeutics.

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A heat-shock response regulated by the PfAP2-HS transcription factor protects human malaria parasites from febrile temperatures

Cited by 42 publications

References 70 publications

RNA Secondary Structurome Revealed Distinct Thermoregulation in Plasmodium falciparum

RNA Secondary Structurome Revealed Distinct Thermoregulation in Plasmodium falciparum

PfD123 modulates K13-mediated survival and recovery after artemisinin exposure

Identification of Antimalarial Compounds that Inhibit Apicomplexan AP2 Proteins

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