A deep sequencing tool for partitioning clearance rates following antimalarial treatment in polyclonal infections

Evolution, Medicine, and Public Health
Nicole MideoJonathan J Juliano

Abstract

Current tools struggle to detect drug-resistant malaria parasites when infections contain multiple parasite clones, which is the norm in high transmission settings in Africa. Our aim was to develop and apply an approach for detecting resistance that overcomes the challenges of polyclonal infections without requiring a genetic marker for resistance. Clinical samples from patients treated with artemisinin combination therapy were collected from Tanzania and Cambodia. By deeply sequencing a hypervariable locus, we quantified the relative abundance of parasite subpopulations (defined by haplotypes of that locus) within infections and revealed evolutionary dynamics during treatment. Slow clearance is a phenotypic, clinical marker of artemisinin resistance; we analyzed variation in clearance rates within infections by fitting parasite clearance curves to subpopulation data. In Tanzania, we found substantial variation in clearance rates within individual patients. Some parasite subpopulations cleared as slowly as resistant parasites observed in Cambodia. We evaluated possible explanations for these data, including resistance to drugs. Assuming slow clearance was a stable phenotype of subpopulations, simulations predicted that modest i...Continue Reading

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Citations

Dec 3, 2016·Proceedings of the National Academy of Sciences of the United States of America·Christian M ParobekJonathan J Juliano
Mar 29, 2018·PLoS Biology·David A Kennedy, Greg Dwyer
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Jul 3, 2019·Malaria Journal·Angela M EarlyDaniel E Neafsey
Aug 18, 2020·The Journal of Infectious Diseases·Elizabeth Hemming-SchroederGuiyun Yan
Aug 9, 2018·Evolution, Medicine, and Public Health·Silvie HuijbenAndrew F Read
Apr 11, 2018·Evolutionary Applications·Philip L G BirgetNicole Mideo
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Jul 20, 2021·PLoS Computational Biology·Alexander O B WhitlockNicole Mideo

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Methods Mentioned

BETA
genotyping
PCR
amplicon sequencing

Clinical Trials Mentioned

NCT01280162

Software Mentioned

R
SeekDeep
MiSeq

Related Concepts

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Antimalarial Agents

Antimalarial agents, also known as antimalarials, are designed to prevent or cure malaria. Discover the latest research on antimalarial agents here.