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

Amit Kumar Subudhi, Judith L. Green, Rohit Satyam, Rahul P. Salunke, Todd Lenz, Muhammad Shuaib, Ioannis Isaioglou, Steven Abel, Mohit Gupta, Luke Esau, Tobias Mourier, Raushan Nugmanova, Sara Mfarrej, Rupali Shivapurkar, Zenaida Stead, Fathia Ben Rached, Yogesh Ostwal, Rachid Sougrat, Ashraf Dada, Abdullah Fuaad KadamanyWolfgang Fischle, Jasmeen Merzaban, Ellen Knuepfer, David J.P. Ferguson, Ishaan Gupta, Karine G. Le Roch, Anthony A. Holder*, Arnab Pain*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)2154-2169
Number of pages16
JournalNature Microbiology
Volume8
Issue number11
DOIs
StatePublished - Nov 2023

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Applied Microbiology and Biotechnology
  • Genetics
  • Microbiology (medical)
  • Cell Biology

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