Molecular surveillance uncovers resistance emerging in Myanmar & early results in Africa

9 September 2014

It was only a few months ago that we read the ground-breaking news in Nature that mutations in the Kelch 13 gene of  P. falciparum were identified as the key molecular marker of artemisinin resistance in Cambodia. This discovery raised the hope that molecular approaches could be used to quickly define the extent of the artemisinin resistance, and target appropriate public health responses.

Since the slow parasite clearance was first defined in 2009, the major worry has been that resistant parasites would spread from their Cambodian heartland, first to other areas in Southeast Asia, and then to the rest of the malaria endemic world. 

The reality of this ongoing concern was recently underlined with the publication of a study into the spread of artemisinin resistance in the New England Journal of Medicine.  This large collaboration surveyed 13 sites across Southeast Asia; their results expanded greatly the number of genetic variations of Kelch 13, or K13, observed in parasites from the Mekong region, and documented the spread of resistant parasites out of Cambodia.

Now, two articles that deepen our understanding of this important story have just been published in the Journal of Infectious Diseases.

The first paper, involving a large number of collaborators led by Prof Chris Plowe at the University of Maryland, analysed additional samples from the Mekong region, correlating  slow clearance of malaria parasites with the presence of parasites that carry amino acid changes in a specific “paddle region” of the K13 gene. They also document the spread of slow clearing Cambodian malaria parasites with K13 mutations in both directions from Cambodia into Vietnam, and Myanmar.

But there is a new twist in the story.  Two genes that carry K13 mutations defined in Cambodia were identified in parasites from Myanmar, but they had not spread from Cambodia; they arose independently in parasites in their Myanmar location.  These newly resistant parasites demonstrate that elimination of the resistant parasites in the Mekong is not the only response required.  We must also design methods to identify new sites where resistant parasites have emerged independently.

The second article is the first to use surveillance of parasite genomes to begin this important search for parasites outside of the Mekong region that might already be artemisinin resistant.  A group of colleagues working in Africa collaborated with Dr’s Steve Taylor and Jonathan Juliano, at Duke University Medical Center and the University of North Carolina, to apply a fast, sensitive analytical method to survey more than 1000 parasites. They analysed genomes of the parasites to determine whether they carry mutations in the key paddle region of K13. 

We found parasites that carried “suspect” mutations in all 14 sites surveyed across sub-Saharan Africa. The prevalence of these mutations was in the range of a few percent in most places, though 2 sites in the Western part of the Democratic Republic of Congo were much higher.” says Dr Jon Juliano, corresponding author of the study. “Since the distributions of the K13 mutant parasites are not yet correlated with an artemisinin resistant phenotype, further approaches will have to be designed to define whether these mutations also demonstrate reduced susceptibility to artemisinin.”

This somewhat startling result raises many questions.  Most importantly: do these K13 mutant parasites also show reduced susceptibility to artemisinins?  Will the K13 “paddle” mutants be a reliable marker for an artemisinin resistant phenotype? There will be soon, no doubt, more information on the prevalence of parasites with mutant K13 genotypes from other regions, but is that genotype correlated with artemisinin responses in these new locations?

We’ll share the latest news on our website and welcome your feedback, email: molecular [at] wwarn [dot] org.

Read these latest papers:

Christopher V. Plowe et al. Independent emergence of Plasmodium falciparum artemisinin resistance mutations in Southeast Asia. The Journal of Infectious Diseases; doi: 10.1093/infdis/jiu491. First published online September 1, 2014.

Absence of putative Plasmodium falciparum artemisinin resistance mutations in sub-Saharan Africa: A molecular epidemiologic study. The Journal of Infectious Diseases; doi: 10.1093/infdis/jiu467. First published online September 1, 2014.

Carol Sibley. Artemisinin resistance: the more we know, the more complicated it appears. Journal of Infectious Diseases; doi:10.1093/infdis/jiu469. First published online September 1, 2014

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