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Malaria Studies Describe Transcription, Mutation Features in Drug-Resistant Parasites

NEW YORK (GenomeWeb) – A pair of studies appearing online today in Science are unraveling the molecular roots of resistance to a malaria drug called artemisinin in the parasite Plasmodium falciparum

In one case, a team led by investigators at Singapore's Nanyang Technological University tracked transcriptional patterns in P. falciparum isolates that had been collected from more than 1,000 patients with acute malaria. In this set of parasites, artemisinin-resistance was linked to a jump in expression by genes involved in a protein repair pathway known as the unfolded protein response, together with lagging progression across a stage of the parasite's development known as the ring-stage.

"[T]he malaria parasite increased its capacity to repair the damage caused by the anti-malarial drug which gives it a higher chance of survival," the study's first author Sachel Mok, a biological sciences researcher at the Nanyang Technological University, said in a statement. "Second, because the drug is more effective against the parasite at its later stage of its development, the parasite slowed down its growth so it could survive longer in the younger stages."

"Investigating these two phenomena in P. falciparum may improve our understanding of the molecular basis of artemisinin resistance and facilitate the development of new strategies to counter the threat it poses to global malaria control and elimination," Mok and colleagues wrote.

Although the advent of artemisinin treatment has put a dent in malaria's toll around the world, there is concern about the rising tide of resistance to the drug in Cambodia, Thailand, Myanmar, and other parts of Southeast Asia.

Past studies have hinted that so-called propeller polymorphisms in a P. falciparum gene called K13 are useful for predicting which strains will be able to withstand artemisinin treatment. Even so, additional work was needed to explore this relationship and to track the broader parasite changes that accompany resistance.

To explore the latter in more detail, Mok and colleagues used arrays to measure expression levels for nearly 5,000 P. falciparum genes in 1,043 isolates collected in vivo from blood samples of individuals with acute malaria living in more than a dozen regions in Southeast Asia or Africa where malaria is endemic.

The parasites clustered in three gene expression groups that largely coincided with P. falciparum developmental stage. But the team also identified transcriptional features linked to features with clinical significance, including artemisinin resistance, which seemed to span the clusters.

When the researchers specifically scrutinized parasites from the ring-stage of P. falciparum development, they found that parasites showing delayed drug clearance — a feature linked to artemisinin resistance — tended to show a dip in representation by more than 500 genes.

On the other hand, they noted that expression for 487 genes was enhanced in parasites suspected of resistance — a set that included genes coding for components of protein transport, endoplasmic reticulum, unfolded protein response, and other pathways. 

Among the downregulated genes found in parasites with K13 gene mutations and other artemisinin resistance features, meanwhile, were players from DNA replication pathways. That, said the study's authors, supports the notion that resistance is linked to sluggish Plasmodium progression through the ring-stage of development.

In an accompanying Science study, an independent team from the US, Cambodia, and France presented data verifying that propeller mutations in the K13 gene can lead to artemisinin resistance in P. falciparum.

For that investigation, researchers looked at how well parasites with genetically modified versions of K13 fared when treated with artemisinin in the lab. Their results revealed reduced resistance in Cambodian isolates in which mutant K13 was replaced with a version of the gene missing the propeller mutations.

While between 13 percent and 49 percent of the original isolates survived after treatment, the team reported, survival declined to between 0.3 percent and 2.4 percent when resistance-related mutations in K13 were axed. 

Introducing the K13 mutations into a wild type P. falciparum strain led to greater-than-usual survival following artemisinin exposure, jumping from as low as 0.6 percent survival to between 2 percent and 29 percent survival.

Based on their findings, authors of that study argued that the research "offers a conclusive rationale for a global K13 sequencing effort to track the spread of [artemisinin] resistance and mitigate its impact on malaria treatment and control programs, particularly in hyper-endemic regions in Africa."

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