The Plasmodium berghei RC strain is highly diverged and harbors putatively novel drug resistance variants

Warangkhana Songsungthong; Supasak Kulawonganunchai; Alisa Wilantho; Sissades Tongsima; Pongpisid Koonyosying; Chairat Uthaipibull; Sumalee Kamchonwongpaisan; Philip J Shaw

doi:10.7717/peerj.3766

The Plasmodium berghei RC strain is highly diverged and harbors putatively novel drug resistance variants

PeerJ. 2017 Oct 5:5:e3766. doi: 10.7717/peerj.3766. eCollection 2017.

Authors

Warangkhana Songsungthong^{1

2}, Supasak Kulawonganunchai³, Alisa Wilantho³, Sissades Tongsima³, Pongpisid Koonyosying¹, Chairat Uthaipibull¹, Sumalee Kamchonwongpaisan¹, Philip J Shaw¹

Affiliations

¹ Protein-Ligand Engineering and Molecular Biology Laboratory, Medical Molecular Biology Research Unit, National Center for Genetic Engineering and Biotechnology (BIOTEC), National Science and Technology Development Agency (NSTDA), Pathum Thani, Thailand.
² Biomolecular Analysis and Application Laboratory, Biosensing Technology Research Unit, National Center for Genetic Engineering and Biotechnology (BIOTEC), National Science and Technology Development Agency (NSTDA), Pathum Thani, Thailand.
³ Biostatistics and Bioinformatics Laboratory, Genome Technology Research Unit, National Center for Genetic Engineering and Biotechnology (BIOTEC), National Science and Technology Development Agency (NSTDA), Pathum Thani, Thailand.

Abstract

Background: The current first line drugs for treating uncomplicated malaria are artemisinin (ART) combination therapies. However, Plasmodium falciparum parasites resistant to ART and partner drugs are spreading, which threatens malaria control efforts. Rodent malaria species are useful models for understanding antimalarial resistance, in particular genetic variants responsible for cross resistance to different compounds.

Methods: The Plasmodium berghei RC strain (PbRC) is described as resistant to different antimalarials, including chloroquine (CQ) and ART. In an attempt to identify the genetic basis for the antimalarial resistance trait in PbRC, its genome was sequenced and compared with five other previously sequenced P. berghei strains.

Results: We found that PbRC is eight-fold less sensitive to the ART derivative artesunate than the reference strain PbANKA. The genome of PbRC is markedly different from other strains, and 6,974 single nucleotide variants private to PbRC were identified. Among these PbRC private variants, non-synonymous changes were identified in genes known to modulate antimalarial sensitivity in rodent malaria species, including notably the ubiquitin carboxyl-terminal hydrolase 1 gene. However, no variants were found in some genes with strong evidence of association with ART resistance in P. falciparum such as K13 propeller protein.

Discussion: The variants identified in PbRC provide insight into P. berghei genome diversity and genetic factors that could modulate CQ and ART resistance in Plasmodium spp.

Keywords: Artemisinin; Chloroquine; Genome; Malaria; Plasmodium berghei RC.

Grants and funding

This work was supported by the National Center for Genetic Engineering and Biotechnology (BIOTEC), Thailand, (grant nos. P1300635 and P1300105 to WS), BIOTEC Platform Technology, Thailand (no. P1551103 to PJS), the Howard Hughes Medical Institute, USA (no. 55005512 to SK), the National Science and Technology Development Agency’s Cluster Program Management, Thailand (no. P1450883 to SK) and the Thailand Research Fund (no. RSA5880064 to CU and no. RSA5860081 to ST). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.