PfHDAC1 is an essential regulator of P. falciparum asexual proliferation and host cell invasion genes with a dynamic genomic occupancy responsive to artemisinin stress

• Published in: mBio Vol. 15; no. 6; p. e0237723
• Main Authors: Kanyal, Abhishek, Deshmukh, Bhagyashree, Davies, Heledd, Mamatharani, D. V., Farheen, Dilsha, Treeck, Moritz, Karmodiya, Krishanpal
• Format: Journal Article
• Language: English
• Published: United States American Society for Microbiology 12.06.2024
• Subjects: Antimalarials - pharmacology; artemisinin resistance; Artemisinins - pharmacology; Erythrocytes - parasitology; histone deacetylase; Histone Deacetylase 1 - genetics; Histone Deacetylase 1 - metabolism; Humans; malaria; Malaria, Falciparum - parasitology; Parasitology; PfHDAC1; Plasmodium falciparum; Plasmodium falciparum - drug effects; Plasmodium falciparum - genetics; Plasmodium falciparum - growth & development; Protozoan Proteins - genetics; Protozoan Proteins - metabolism; Reproduction, Asexual - genetics; Research Article; transcriptomics; artemisinin resistance; transcriptomics; Plasmodium falciparum; PfHDAC1; malaria; histone deacetylase
• ISSN: 2150-7511; 2150-7511
• DOI: 10.1128/mbio.02377-23

Malaria is a major public health problem, with the parasite Plasmodium falciparum causing most of the malaria-associated mortality. It is spread by the bite of infected mosquitoes and results in symptoms such as cyclic fever, chills, and headache. However, if left untreated, it can quickly progress to a more severe and life-threatening form. The World Health Organization currently recommends the use of artemisinin combination therapy, and it has worked as a gold standard for many years. Unfortunately, certain countries in southeast Asia and Africa, burdened with a high prevalence of malaria, have reported cases of drug-resistant infections. One of the major problems in controlling malaria is the emergence of artemisinin resistance. Population genomic studies have identified mutations in the Kelch13 gene as a molecular marker for artemisinin resistance. However, several reports thereafter indicated that Kelch13 is not the main mediator but rather hinted at transcriptional deregulation as a major determinant of drug resistance. Earlier, we identified PfGCN5 as a global regulator of stress-responsive genes, which are known to play a central role in artemisinin resistance generation. In this study, we have identified PfHDAC1, a histone deacetylase as a cell cycle regulator, playing an important role in artemisinin resistance generation. Taken together, our study identified key transcriptional regulators that play an important role in artemisinin resistance generation.