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ORIGINAL RESEARCH article

Front. Cell. Infect. Microbiol.
Sec. Clinical Microbiology
Volume 14 - 2024 | doi: 10.3389/fcimb.2024.1521152

Plasmodium falciparum transcription factor AP2-06B is mutated at high frequency in Southeast Asia but does not associate with drug resistance

Provisionally accepted
Qiyang Shi Qiyang Shi 1Changhong Wang Changhong Wang 2Wenluan Yang Wenluan Yang 1Xiaoqin Ma Xiaoqin Ma 1Jianxia Tang Jianxia Tang 1Jiayao Zhang Jiayao Zhang 1Guoding Zhu Guoding Zhu 1Yinlong Wang Yinlong Wang 1Yaobao Liu Yaobao Liu 1*Xiaoqin He Xiaoqin He 1*
  • 1 Jiangsu Institute of Parasitic Diseases (JIPD), Wuxi, China
  • 2 Research Center for Translation Medicine, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China

The final, formatted version of the article will be published soon.

    A continuing challenge for malaria control is the ability of Plasmodium falciparum to develop resistance to antimalarial drugs. Members within the Plasmodium transcription factor family AP2 regulate the growth and development of the parasite, and are also thought to be involved in unclear aspects of drug resistance. Here we screened for single nucleotide polymorphisms (SNPs) within the AP2 family and identified 6 non-synonymous mutations within AP2-06B (PF3D7_0613800), with allele frequencies greater than 0.05. One mutation, K3124R, was located in a PfAP2-06B AP2 domain.To investigate transcriptional regulation by PfAP2-06B, ChIP-seq assays were performed on 3D7/PfAP2-06B-GFP schizonts using antibodies against GFP. The DNA sequences of the artemisinin-resistant CWX and the quinoline-resistant strains PfDd2 and Pf7G8 were analyzed for the genetic diversity of AP2-06B, compared with the Pf3D7 strain as a reference sequence. To determine whether AP2-06B can alter the expression of pfk13 and pfcrt, as well as cause artemisinin and quinoline resistance in Plasmodium, we generated both a K3124R mutation and conditional knockdown of AP2-06B in Pf3D7 using CRISPR/Cas9mediated genome editing.Results: ChIP-Seq analysis showed that AP2-06B can bind to the loci of the Plasmodium genes pfk13 and pfcrt. The AP2-06B K3124R mutation was also found in the artemisinin-resistant parasite strain CWX and the chloroquine-resistant strains Dd2 and 7G8. Contrary to expectation, Pf3D7 Plasmodium lines modified by either K3124R mutation of AP2-06B or conditional knockdown of AP2-06B did not have altered sensitivity to artemisinin or quinolines by modulating pfk13 or pfcrt expression.Discussion: AP2-06B was predicted to be associated with artemisinin and quinoline resistance, but no change in resistance was observed after mutation or conditional knockdown. Given the multigenic nature of resistance, it might be difficult to recreate a resistance phenotype. In conclusion, whether AP2-06B regulates the development of artemisinin or quinoline resistance remains to be studied.

    Keywords: drug-resistant, AP2-06B, PfK13, Pfcrt, AP2

    Received: 01 Nov 2024; Accepted: 02 Dec 2024.

    Copyright: © 2024 Shi, Wang, Yang, Ma, Tang, Zhang, Zhu, Wang, Liu and He. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence:
    Yaobao Liu, Jiangsu Institute of Parasitic Diseases (JIPD), Wuxi, China
    Xiaoqin He, Jiangsu Institute of Parasitic Diseases (JIPD), Wuxi, China

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