# Novel Genetic Mechanism of Artemisinin Resistance for Malaria

> **NIH NIH R01** · HARVARD UNIVERSITY D/B/A HARVARD SCHOOL OF PUBLIC HEALTH · 2021 · $694,949

## Abstract

Recent progress in malaria control has reduced the incidence and saved the lives of hundreds of
thousands of children, but effective strategies depend on a combination of measures that includes special
emphasis on artemisinin-based combination therapies (ACTs). The predicted dire consequences of the
evolution and spread of artemisinin (ART) resistance have been borne out tragically in Southeast Asia, where
ART resistance evolved quickly and spread rapidly. The ART-resistance determinants reside in the propeller
domain of the Pfkelch13 locus (K13), which is thought to facilitate protein quality control and modulate stress
responses. Importantly, the K13 determinant was first identified through five-year in vitro selection and
sequencing of a resistant strain from Tanzania; K13 was only later confirmed in the field in Southeast Asia.
 Were ART resistance to take hold and spread in Africa it would be truly catastrophic. Why it has not is open
to speculation, however one possibility is because K13 effects are strongly dependent on genetic background,
and there are significant genetic differences between African parasite and SE Asian lineages.
 But persistent, strong selection pressure from ART treatment in Africa will—as every evolutionary biologist
knows—result almost inevitably in the evolution of resistance determinants in Africa. Based on the hypothesis
that ART resistance might depend on genetic background, four years ago (prior to the K13 report) we began
selecting independent replicate lines of parasites from Senegal. We are now able to report that high-level
resistance has evolved in three independent lines. Our ART resistance lines show all of the known in
vitro phenotypic hallmarks of clinical ART resistance, but they are not K13 mutants!
 Remarkably, three independent selected lines each contain a different mutation in the gene
PF3D7_1251200, which encodes Coronin, one of a family of WD-repeat proteins containing a beta propeller
structure. The importance of Pf1251200 has already been demonstrated experimentally in our laboratory using
CRISPR/Cas9 replacements.
 These findings demonstrate the existence of at least two distinct genetic mechanisms of ART
resistance. Investigating the Pf1251200 mutants and their interactions with K13 and other genes will help
elucidate the mechanism of action of artemisinin, which is still unknown, and perhaps more important will
provide markers for early detection of non-K13 ART resistance in clinical settings in Africa as well as SE Asia
where a significant proportion of ART-resistant isolates have no mutations in K13.

## Key facts

- **NIH application ID:** 10201429
- **Project number:** 5R01AI099105-08
- **Recipient organization:** HARVARD UNIVERSITY D/B/A HARVARD SCHOOL OF PUBLIC HEALTH
- **Principal Investigator:** Daniel L HARTL
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $694,949
- **Award type:** 5
- **Project period:** 2013-04-05 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10201429

## Citation

> US National Institutes of Health, RePORTER application 10201429, Novel Genetic Mechanism of Artemisinin Resistance for Malaria (5R01AI099105-08). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10201429. Licensed CC0.

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