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DNA-binding protein PfAP2-P regulates parasite pathogenesis during malaria parasite blood stages.

ABSTRACT: Malaria-associated pathogenesis such as parasite invasion, egress, host cell remodelling and antigenic variation requires concerted action by many proteins, but the molecular regulation is poorly understood. Here we have characterized an essential Plasmodium-specific Apicomplexan AP2 transcription factor in Plasmodium falciparum (PfAP2-P; pathogenesis) during the blood-stage development with two peaks of expression. An inducible knockout of gene function showed that PfAP2-P is essential for trophozoite development, and critical for var gene regulation, merozoite development and parasite egress. Chromatin immunoprecipitation sequencing data collected at timepoints matching the two peaks of pfap2-p expression demonstrate PfAP2-P binding to promoters of genes controlling trophozoite development, host cell remodelling, antigenic variation and pathogenicity. Single-cell RNA sequencing and fluorescence-activated cell sorting revealed de-repression of most var genes in Δpfap2-p parasites. Δpfap2-p parasites also overexpress early gametocyte marker genes, indicating a regulatory role in sexual stage conversion. We conclude that PfAP2-P is an essential upstream transcriptional regulator at two distinct stages of the intra-erythrocytic development cycle.

SUBMITTER: Subudhi AK

PROVIDER: S-EPMC10627835 | biostudies-literature | 2023 Nov

REPOSITORIES: biostudies-literature

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DNA-binding protein PfAP2-P regulates parasite pathogenesis during malaria parasite blood stages.

Subudhi Amit Kumar AK Green Judith L JL Satyam Rohit R Salunke Rahul P RP Lenz Todd T Shuaib Muhammad M Isaioglou Ioannis I Abel Steven S Gupta Mohit M Esau Luke L Mourier Tobias T Nugmanova Raushan R Mfarrej Sara S Shivapurkar Rupali R Stead Zenaida Z Rached Fathia Ben FB Ostwal Yogesh Y Sougrat Rachid R Dada Ashraf A Kadamany Abdullah Fuaad AF Fischle Wolfgang W Merzaban Jasmeen J Knuepfer Ellen E Ferguson David J P DJP Gupta Ishaan I Le Roch Karine G KG Holder Anthony A AA Pain Arnab A

Nature microbiology 20231026 11

Malaria-associated pathogenesis such as parasite invasion, egress, host cell remodelling and antigenic variation requires concerted action by many proteins, but the molecular regulation is poorly understood. Here we have characterized an essential Plasmodium-specific Apicomplexan AP2 transcription factor in Plasmodium falciparum (PfAP2-P; pathogenesis) during the blood-stage development with two peaks of expression. An inducible knockout of gene function showed that PfAP2-P is essential for trop ...[more]

PMID: 37884813

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Project description:The pathogenicity of the malaria parasites results from their ability to invade and remodel red blood cells (RBCs), expressing antigenic variant proteins for immune evasion and survival, and then to egress from the host cell. These sequential processes require concerted actions of a large number of proteins during the intraerythrocytic developmental cycle (IDC)(Boddey and Cowman, 2013; Cowman et al., 2017; Tan and Blackman, 2021), but the molecular basis of the required regulation is only partially understood. Here, we have characterized an essential Apicomplexan AP2 (ApiAP2) transcription factor (we refer to it as PfAP2-MRP; Master Regulator of Pathogenesis) that shows two peaks of expression during the IDC at 16- and 40-hour post-invasion (h.p.i.). When expression of PfAP2-MRP at 40 h.p.i. was disrupted using an inducible gene knockout approach, ∆PfAP2-MRP parasites unable to form mature merozoites and egress from the host RBCs owing to strong down-regulation of several known egress- and invasion-associated genes, in addition to several novel hypothetical genes thought to be involved in these key life cycle processes. Disruption of PfAP2-MRP expression at 16 h.p.i. results in transcriptional activation of the majority of silenced var genes observed at both bulk and single-cell level. This is also reflected by a significantly higher level of immuno-recognition of the exported proteins on the ∆PfAP2-MRP parasite-infected RBCs by pooled sera from malaria-exposed individuals from an endemic region. In addition, overexpression of many early gametocyte marker genes was also observed in ∆PfAP2-MRP parasites at both 40 h.p.i., and at 16 h.p.i. PfAP2-MRP directly regulates these genes by binding to their promoter region or indirectly through 14 other downstream AP2 transcription factors. Taken together, we conclude that PfAP2-MRP is an upstream transcriptional regulator that participates in mutually exclusive expression patterns shown by the var family of genes and is a critical determinant of parasite's growth during the IDC.

Dataset Information

DNA-binding protein PfAP2-P regulates parasite pathogenesis during malaria parasite blood stages.

Publications

DNA-binding protein PfAP2-P regulates parasite pathogenesis during malaria parasite blood stages.

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