User login
Plasmodium falciparum
Credit: CDC/Mae Melvin
Researchers say they’ve uncovered the complex genetic architecture that enables the malaria parasite Plasmodium falciparum to develop resistance to the antimalarial drug artemisinin.
The team found evidence to suggest that 20 mutations in a single gene work with background mutations in 4 other genes to promote resistance.
The group believes their findings, published in Nature Genetics, could help improve early detection of emerging artemisinin resistance.
To make their discovery, the researchers analyzed 1612 samples from subjects at 15 locations in Southeast Asia and Africa. The team performed P falciparum genome sequencing and genotype calling at more than 600,000 single-nucleotide polymorphism positions on all samples.
The work revealed 20 mutations in the kelch13 gene, a known artemisinin resistance marker, that appear to work in concert with a set of background mutations in 4 other genes—fd, arps10, mdr2, and crt—to support artemisinin resistance.
“Our findings suggest that these background mutations emerged with limited impact on artemisinin resistance—until mutations occurred in the kelch13 gene,” said Roberto Amato, PhD, of the Wellcome Trust Sanger Institute in Oxford, UK.
“It’s similar to what we see with precancerous cells, which accumulate genetic changes but only become malignant when they acquire critical driver mutations that kick off growth.”
The variety of kelch13 mutations associated with artemisinin resistance makes it difficult to use this gene alone as a marker for genetic surveillance.
Monitoring parasite populations for a specific genetic background—in this case, a fixed set of 4 well-defined mutations in fd, arps10, mdr2, and crt—could allow researchers to assess the likelihood of new resistance-causing mutations emerging in different locations, helping to target high-risk regions before resistant parasites take hold.
“We are at a pivotal point for malaria control,” said Nick Day, MBBS, of the Mahidol-Oxford Tropical Medicine Research Unit (MORU) in Bangkok, Thailand.
“While malaria deaths have been halved, this progress is at risk if artemisinin ceases to be effective. We need to use every tool at our disposal to protect this drug. Monitoring parasites for background mutations could provide an early warning system to identify areas at risk for artemisinin resistance.”
The researchers also uncovered new clues about how artemisinin resistance has evolved in Southeast Asia. By comparing parasites from Cambodia, Vietnam, Laos, Thailand, Myanmar, and Bangladesh, the team found that the distribution of different kelch13 mutations is localized within relatively well-defined geographical areas.
Although artemisinin-resistant parasites appear to have migrated across national borders, this only happened on a limited scale. In fact, the most widespread kelch13 mutation, C580Y, seems to have emerged independently on several occasions.
Parasites along the Thailand-Myanmar border appear to have acquired C580Y separately from those in Cambodia and Vietnam. But parasite populations in both regions possess the genetic background mutations, even though they are clearly genetically distinct.
“We don’t yet know the role of these background mutations,” said Olivo Miotto, PhD, also of MORU. “Some may not affect drug resistance directly but, rather, provide an environment where drug-resistance mutations are tolerated.”
“Since kelch13 has hardly changed in 50 million years of Plasmodium evolution, we can assume that this gene is essential to parasite survival. Therefore, kelch13 mutations may severely handicap mutant parasites, compromising their survival unless some other change can counteract this negative effect.”
Mutations in the kelch13 gene were present, yet rare, in Africa. But they weren’t associated with artemisinin resistance and lacked the genetic background present in artemisinin-resistant parasites in Southeast Asia. This provides some reassurance for public health authorities working to prevent the spread of artemisinin resistance to Africa, where most malaria deaths occur.
“These data serve as a reminder of how crucial surveillance and elimination programs are,” said Dominic Kwiatkowski, MBBS, of the Wellcome Trust Sanger Institute.
“At present, artemisinin resistance appears to be largely confined to Southeast Asia, but the situation might change as the parasite population continues to evolve. By linking genomic data with clinical data, we’re developing a better understanding of the multiple genetic factors involved in the emergence of resistance, and that is starting to provide vital clues about how to prevent its spread.” 
Plasmodium falciparum
Credit: CDC/Mae Melvin
Researchers say they’ve uncovered the complex genetic architecture that enables the malaria parasite Plasmodium falciparum to develop resistance to the antimalarial drug artemisinin.
The team found evidence to suggest that 20 mutations in a single gene work with background mutations in 4 other genes to promote resistance.
The group believes their findings, published in Nature Genetics, could help improve early detection of emerging artemisinin resistance.
To make their discovery, the researchers analyzed 1612 samples from subjects at 15 locations in Southeast Asia and Africa. The team performed P falciparum genome sequencing and genotype calling at more than 600,000 single-nucleotide polymorphism positions on all samples.
The work revealed 20 mutations in the kelch13 gene, a known artemisinin resistance marker, that appear to work in concert with a set of background mutations in 4 other genes—fd, arps10, mdr2, and crt—to support artemisinin resistance.
“Our findings suggest that these background mutations emerged with limited impact on artemisinin resistance—until mutations occurred in the kelch13 gene,” said Roberto Amato, PhD, of the Wellcome Trust Sanger Institute in Oxford, UK.
“It’s similar to what we see with precancerous cells, which accumulate genetic changes but only become malignant when they acquire critical driver mutations that kick off growth.”
The variety of kelch13 mutations associated with artemisinin resistance makes it difficult to use this gene alone as a marker for genetic surveillance.
Monitoring parasite populations for a specific genetic background—in this case, a fixed set of 4 well-defined mutations in fd, arps10, mdr2, and crt—could allow researchers to assess the likelihood of new resistance-causing mutations emerging in different locations, helping to target high-risk regions before resistant parasites take hold.
“We are at a pivotal point for malaria control,” said Nick Day, MBBS, of the Mahidol-Oxford Tropical Medicine Research Unit (MORU) in Bangkok, Thailand.
“While malaria deaths have been halved, this progress is at risk if artemisinin ceases to be effective. We need to use every tool at our disposal to protect this drug. Monitoring parasites for background mutations could provide an early warning system to identify areas at risk for artemisinin resistance.”
The researchers also uncovered new clues about how artemisinin resistance has evolved in Southeast Asia. By comparing parasites from Cambodia, Vietnam, Laos, Thailand, Myanmar, and Bangladesh, the team found that the distribution of different kelch13 mutations is localized within relatively well-defined geographical areas.
Although artemisinin-resistant parasites appear to have migrated across national borders, this only happened on a limited scale. In fact, the most widespread kelch13 mutation, C580Y, seems to have emerged independently on several occasions.
Parasites along the Thailand-Myanmar border appear to have acquired C580Y separately from those in Cambodia and Vietnam. But parasite populations in both regions possess the genetic background mutations, even though they are clearly genetically distinct.
“We don’t yet know the role of these background mutations,” said Olivo Miotto, PhD, also of MORU. “Some may not affect drug resistance directly but, rather, provide an environment where drug-resistance mutations are tolerated.”
“Since kelch13 has hardly changed in 50 million years of Plasmodium evolution, we can assume that this gene is essential to parasite survival. Therefore, kelch13 mutations may severely handicap mutant parasites, compromising their survival unless some other change can counteract this negative effect.”
Mutations in the kelch13 gene were present, yet rare, in Africa. But they weren’t associated with artemisinin resistance and lacked the genetic background present in artemisinin-resistant parasites in Southeast Asia. This provides some reassurance for public health authorities working to prevent the spread of artemisinin resistance to Africa, where most malaria deaths occur.
“These data serve as a reminder of how crucial surveillance and elimination programs are,” said Dominic Kwiatkowski, MBBS, of the Wellcome Trust Sanger Institute.
“At present, artemisinin resistance appears to be largely confined to Southeast Asia, but the situation might change as the parasite population continues to evolve. By linking genomic data with clinical data, we’re developing a better understanding of the multiple genetic factors involved in the emergence of resistance, and that is starting to provide vital clues about how to prevent its spread.”
Plasmodium falciparum
Credit: CDC/Mae Melvin
Researchers say they’ve uncovered the complex genetic architecture that enables the malaria parasite Plasmodium falciparum to develop resistance to the antimalarial drug artemisinin.
The team found evidence to suggest that 20 mutations in a single gene work with background mutations in 4 other genes to promote resistance.
The group believes their findings, published in Nature Genetics, could help improve early detection of emerging artemisinin resistance.
To make their discovery, the researchers analyzed 1612 samples from subjects at 15 locations in Southeast Asia and Africa. The team performed P falciparum genome sequencing and genotype calling at more than 600,000 single-nucleotide polymorphism positions on all samples.
The work revealed 20 mutations in the kelch13 gene, a known artemisinin resistance marker, that appear to work in concert with a set of background mutations in 4 other genes—fd, arps10, mdr2, and crt—to support artemisinin resistance.
“Our findings suggest that these background mutations emerged with limited impact on artemisinin resistance—until mutations occurred in the kelch13 gene,” said Roberto Amato, PhD, of the Wellcome Trust Sanger Institute in Oxford, UK.
“It’s similar to what we see with precancerous cells, which accumulate genetic changes but only become malignant when they acquire critical driver mutations that kick off growth.”
The variety of kelch13 mutations associated with artemisinin resistance makes it difficult to use this gene alone as a marker for genetic surveillance.
Monitoring parasite populations for a specific genetic background—in this case, a fixed set of 4 well-defined mutations in fd, arps10, mdr2, and crt—could allow researchers to assess the likelihood of new resistance-causing mutations emerging in different locations, helping to target high-risk regions before resistant parasites take hold.
“We are at a pivotal point for malaria control,” said Nick Day, MBBS, of the Mahidol-Oxford Tropical Medicine Research Unit (MORU) in Bangkok, Thailand.
“While malaria deaths have been halved, this progress is at risk if artemisinin ceases to be effective. We need to use every tool at our disposal to protect this drug. Monitoring parasites for background mutations could provide an early warning system to identify areas at risk for artemisinin resistance.”
The researchers also uncovered new clues about how artemisinin resistance has evolved in Southeast Asia. By comparing parasites from Cambodia, Vietnam, Laos, Thailand, Myanmar, and Bangladesh, the team found that the distribution of different kelch13 mutations is localized within relatively well-defined geographical areas.
Although artemisinin-resistant parasites appear to have migrated across national borders, this only happened on a limited scale. In fact, the most widespread kelch13 mutation, C580Y, seems to have emerged independently on several occasions.
Parasites along the Thailand-Myanmar border appear to have acquired C580Y separately from those in Cambodia and Vietnam. But parasite populations in both regions possess the genetic background mutations, even though they are clearly genetically distinct.
“We don’t yet know the role of these background mutations,” said Olivo Miotto, PhD, also of MORU. “Some may not affect drug resistance directly but, rather, provide an environment where drug-resistance mutations are tolerated.”
“Since kelch13 has hardly changed in 50 million years of Plasmodium evolution, we can assume that this gene is essential to parasite survival. Therefore, kelch13 mutations may severely handicap mutant parasites, compromising their survival unless some other change can counteract this negative effect.”
Mutations in the kelch13 gene were present, yet rare, in Africa. But they weren’t associated with artemisinin resistance and lacked the genetic background present in artemisinin-resistant parasites in Southeast Asia. This provides some reassurance for public health authorities working to prevent the spread of artemisinin resistance to Africa, where most malaria deaths occur.
“These data serve as a reminder of how crucial surveillance and elimination programs are,” said Dominic Kwiatkowski, MBBS, of the Wellcome Trust Sanger Institute.
“At present, artemisinin resistance appears to be largely confined to Southeast Asia, but the situation might change as the parasite population continues to evolve. By linking genomic data with clinical data, we’re developing a better understanding of the multiple genetic factors involved in the emergence of resistance, and that is starting to provide vital clues about how to prevent its spread.”