A novel Modulator of Ring Stage Translation (MRST) gene alters artemisinin sensitivity in Plasmodium falciparum

Simmons, C. et al. (2023) A novel Modulator of Ring Stage Translation (MRST) gene alters artemisinin sensitivity in Plasmodium falciparum. mSphere, 8(4), (doi: 10.1128/msphere.00152-23) (PMID:37219373) (PMCID:PMC10449512)

Abstract

The implementation of artemisinin (ART) combination therapies (ACTs) has greatly decreased deaths caused by Plasmodium falciparum malaria, but increasing ACT resistance in Southeast Asia and Africa could reverse this progress. Parasite population genetic studies have identified numerous genes, single-nucleotide polymorphisms (SNPs), and transcriptional signatures associated with altered artemisinin activity with SNPs in the Kelch13 (K13) gene being the most well-characterized artemisinin resistance marker. However, there is an increasing evidence that resistance to artemisinin in P. falciparum is not related only to K13 SNPs, prompting the need to characterize other novel genes that can alter ART responses in P. falciparum. In our previous analyses of P. falciparum piggyBac mutants, several genes of unknown function exhibited increased sensitivity to artemisinin that was similar to a mutant of K13. Further analysis of these genes and their gene co-expression networks indicated that the ART sensitivity cluster was functionally linked to DNA replication and repair, stress responses, and maintenance of homeostatic nuclear activity. In this study, we have characterized PF3D7_1136600, another member of the ART sensitivity cluster. Previously annotated as a conserved Plasmodium gene of unknown function, we now provide putative annotation of this gene as a Modulator of Ring Stage Translation (MRST). Our findings reveal that the mutagenesis of MRST affects gene expression of multiple translation-associated pathways during the early ring stage of asexual development via putative ribosome assembly and maturation activity, suggesting an essential role of MRST in protein biosynthesis and another novel mechanism of altering the parasite’s ART drug response.

• Item Type: Articles
• Additional Information: This work is supported by National Institute of Allergy and Infectious Diseases grants R01AI117017 and R01AI130171.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Otto, Professor Thomas

Creator Roles

Otto, T. D.: Data curation, Investigation, Supervision, Writing – review and editing

• Authors: Simmons, C., Gibbons, J., Wang, C., Pires, C. V., Zhang, M., Siddiqui, F., Oberstaller, J., Casandra, D., Seyfang, A., Cui, L., Otto, T. D., and Adams, J. H.
• College/School: College of Medical Veterinary and Life Sciences > School of Infection & Immunity
• Research Centre: College of Medical Veterinary and Life Sciences > School of Infection & Immunity > Centre for Immunobiology
• Journal Name: mSphere
• Publisher: American Society for Microbiology
• ISSN: 2379-5042
• ISSN (Online): 2379-5042
• Published Online: 23 May 2023
• Copyright Holders: Copyright © 2023 Simmons et al.
• First Published: First published in mSphere 8(4)
• Publisher Policy: Reproduced under a Creative Commons License