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

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

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.

Citation

Subudhi, A. K., Green, J. L., Satyam, R., Salunke, R. P., Lenz, T., Shuaib, M., Isaioglou, I., Abel, S., Gupta, M., Esau, L., Mourier, T., Nugmanova, R., Mfarrej, S., Shivapurkar, R., Stead, Z., Rached, F. B., Ostwal, Y., Sougrat, R., Dada, A., Kadamany, A. F., …Pain, A. (2023). DNA-binding protein PfAP2-P regulates parasite pathogenesis during malaria parasite blood stages. Nature Microbiology, 8(11), 2154-2169. https://doi.org/10.1038/s41564-023-01497-6

• Journal Article Type: Article
• Acceptance Date: Sep 11, 2023
• Online Publication Date: Oct 26, 2023
• Publication Date: Oct 26, 2023
• Deposit Date: Nov 30, 2023
• Publicly Available Date: Dec 4, 2023
• Journal: Nature Microbiology
• Electronic ISSN: 2058-5276
• Publisher: Nature Research
• Peer Reviewed: Peer Reviewed
• Volume: 8
• Issue: 11
• Pages: 2154-2169
• DOI: https://doi.org/10.1038/s41564-023-01497-6
• Keywords: Cell Biology; Microbiology (medical); Genetics; Applied Microbiology and Biotechnology; Immunology; Microbiology
• Additional Information: Received: 9 May 2023; Accepted: 11 September 2023; First Online: 26 October 2023; : The authors declare no competing interests.