Mutant PfCRT Can Mediate Piperaquine Resistance in African Plasmodium falciparum With Reduced Fitness and Increased Susceptibility to Other Antimalarials.

Autor:	Wicht KJ; Department of Microbiology and Immunology, Columbia University Irving Medical Center, New York, New York, USA., Small-Saunders JL; Department of Microbiology and Immunology, Columbia University Irving Medical Center, New York, New York, USA.; Center for Malaria Therapeutics and Antimalarial Resistance, Division of Infectious Diseases, Department of Medicine, Columbia University Irving Medical Center, New York , New York, USA., Hagenah LM; Department of Microbiology and Immunology, Columbia University Irving Medical Center, New York, New York, USA., Mok S; Department of Microbiology and Immunology, Columbia University Irving Medical Center, New York, New York, USA., Fidock DA; Department of Microbiology and Immunology, Columbia University Irving Medical Center, New York, New York, USA.; Center for Malaria Therapeutics and Antimalarial Resistance, Division of Infectious Diseases, Department of Medicine, Columbia University Irving Medical Center, New York , New York, USA.
Jazyk:	angličtina
Zdroj:	The Journal of infectious diseases [J Infect Dis] 2022 Nov 28; Vol. 226 (11), pp. 2021-2029.
DOI:	10.1093/infdis/jiac365
Abstrakt:	Background: Additional therapeutic strategies could benefit efforts to reverse the recent increase in malaria cases in sub-Saharan Africa, which mostly affects young children. A primary candidate is dihydroartemisinin + piperaquine (DHA + PPQ), which is effective for uncomplicated malaria treatment, seasonal malaria chemoprevention, and intermittent preventive treatment. In Southeast Asia, Plasmodium falciparum parasites acquired PPQ resistance, mediated primarily by mutations in the P falciparum chloroquine resistance transporter PfCRT. The recent emergence in Africa of DHA-resistant parasites creates an imperative to assess whether PPQ resistance could emerge in African parasites with distinct PfCRT isoforms. Methods: We edited 2 PfCRT mutations known to mediate high-grade PPQ resistance in Southeast Asia into GB4 parasites from Gabon. Gene-edited clones were profiled in antimalarial concentration-response and fitness assays. Results: The PfCRT F145I mutation mediated moderate PPQ resistance in GB4 parasites but with a substantial fitness cost. No resistance was observed with the PfCRT G353V mutant. Both edited clones became significantly more susceptible to amodiaquine, chloroquine, and quinine. Conclusions: A single PfCRT mutation can mediate PPQ resistance in GB4 parasites, but with a growth defect that may preclude its spread without further genetic adaptations. Our findings support regional use of drug combinations that exert opposing selective pressures on PfCRT. Competing Interests: Potential conflicts of interest. All authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)
Databáze:	MEDLINE
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