Researchers identify genes causing antimalarial drug resistance
Using a pair of powerful genome-search techniques, researchers from the Harvard School of Public Health (HSPH), Harvard University, and the Broad Institute have identified several genes that may be implicated in the malaria parasite's notorious ability to rapidly evade drug treatments. Further testing revealed that one of the genes, when inserted into drug-sensitive parasites, rendered them less vulnerable to three antimalarial drugs.
The successful experiments suggest that the genomic methods are useful tools for probing the genetic mechanisms underlying drug resistance in the Plasmodium falciparum malaria parasite and potentially other types of disease-causing parasites as well.
The study appears online April 21, 2011, in PLoS Genetics, and is timed to coincide with World Malaria Day on April 25.
"Identification of mutations associated with drug resistance helps us understand how the parasite evades the effects of the drug," said Sarah Volkman, senior research scientist at HSPH and a co-senior author of the paper. "Once we understand the processes used by the parasite to avoid the effects of the antimalarial treatment, scientists can develop new drugs that circumvent the strategies employed by the drug-resistant malaria parasite."
In addition, said Volkman, knowing the mutations that signal that a parasite has become resistant to an antimalarial compound allows researchers to develop tools that can be used for monitoring and surveillance of drug-resistant parasites.
Reducing the toll of malaria, which kills nearly a million people a year--mainly young children in sub-Sahara Africa--is a major challenge because of the parasite's talent for swiftly developing resistance to multiple drugs. To counter the shape-shifting parasite's defenses, scientists say they must improve on their meager understanding of the molecular and genetic mechanisms of resistance.
Genetically diverse populations of the blood-borne malaria parasite are endemic in Africa, Asia, and South America. When exposed to antimalarial drugs and the human immune system, Plasmodium falciparum has a remarkable ability to quickly generate resistant clones of parasites, a major obstacle to successful treatment.
For the study, the scientists, including Volkman, Dyann Wirth, and co-first author Daria Van Tyne of HSPH and the Broad, co-first author Danny Park and Pardis Sabeti of the Broad and Harvard University, and Daniel Neafsey and Stephen Schaffner of the Broad, analyzed the DNA of 57 parasites from the three continents, using a high-density genome-wide array that examines more than 17,000 mutations. They also measured the parasites' responses to 13 antimalarial drugs.
The scientists examined diversity of the parasite to identify 20 rapidly evolving loci in the genome, and then carried out a genome-wide association study (GWAS) to identify genetic variants that correlated with or are associated with the drug-resistance trait. These genetic variants are necessarily enriched in the drug-resistant, but not drug-sensitive parasites, allowing the researchers to home in on the candidate genes that are involved in modulating drug responses. That search netted 11 genes implicated in drug resistance one previously known and others discovered for the first time.
Van Tyne pursued one of the novel genes, PF10_0355, for follow-up functional testing. She used an experimental technique that introduced extra copies of the gene from a resistant parasite into a drug-sensitive one, and found that the formerly sensitive parasite was now rendered more resistant to three standard antimalarial agents.
"This demonstration suggests that the gene is involved in modifying parasite drug response," said Van Tyne, a graduate student in the laboratory of Wirth, chair of the Department of Immunology and Infectious Diseases at HSPH and a co-director of the Infectious Disease Initiative at the Broad. "We feel that this is one gene of potentially many that affect drug-resistance mechanisms. We're now working to follow up and understand how these and the other genes identified work."
Drug resistance is a major concern that threatens to undermine global efforts to control or eradicate malaria. Understanding how the parasite is changing before clinical drug resistance is apparent offers some hope that we might be able to extend the useful life of available drugs and identify new effective antimalarials, said Volkman.
More information: "Identification and Functional Validation of the Novel Antimalarial Resistance Locus PF10_0355 in Plasmodium Falciparum," Daria Van Tyne, Daniel J. Park, Stephen F. Schaffner, Daniel E. Neafsey, Elaine Angelino, Joseph F. Cortese, Kayla G. Barnes, David M. Rosen, Amanda K. Lukens, Rachel F. Daniels, Danny A. Milner, Jr., Charles A. Johnson, Ilya Shlyakhter, Sharon R. Grossman, Justin S. Becker, Daniel Yamins, Elinor K. Karlsson, Daouda Ndiaye, Ousmane Sarr, Souleymane Mboup, Christian Happi, Nicholas A. Furlotte, Eleazar Eskin, Hyun Min Kang, Daniel L. Hartl, Bruce W. Birren, Roger C. Wiegand, Eric S. Lander, Dyann F. Wirth, Sarah K. Volkman, Pardis C. Sabeti, PLoS Genetics, online April 21, 2011
Provided by Harvard School of Public Health
- Scientists pinpoint gene linked to drug resistance in malaria Oct 12, 2010 | not rated yet | 0
- New papers offer insights into process of malarial drug resistance Nov 26, 2008 | not rated yet | 0
- Drug-resistant malaria suggests a health policy change for pregnant women and infants Sep 08, 2010 | not rated yet | 0
- How the parasite responsible for severe forms of malaria can resist a major antimalarial agent May 05, 2010 | not rated yet | 0
- Scientists demonstrate feasibility of preventing malaria parasite from becoming sexually mature Jun 02, 2008 | not rated yet | 0
- Motion perception revisited: High Phi effect challenges established motion perception assumptions Apr 23, 2013 | 3 / 5 (2) | 2
- Anything you can do I can do better: Neuromolecular foundations of the superiority illusion (Update) Apr 02, 2013 | 4.5 / 5 (11) | 5
- The visual system as economist: Neural resource allocation in visual adaptation Mar 30, 2013 | 5 / 5 (2) | 9
- Separate lives: Neuronal and organismal lifespans decoupled Mar 27, 2013 | 4.9 / 5 (8) | 0
- Sizing things up: The evolutionary neurobiology of scale invariance Feb 28, 2013 | 4.8 / 5 (10) | 14
Classical and Quantum Mechanics via Lie algebras
Apr 15, 2011 I'd like to open a discussion thread for version 2 of the draft of my book ''Classical and Quantum Mechanics via Lie algebras'', available online at http://lanl.arxiv.org/abs/0810.1019 , and for the...
- More from Physics Forums - Independent Research
More news stories
Two mutations central to the development of infantile myofibromatosis (IM)—a disorder characterized by multiple tumors involving the skin, bone, and soft tissue—may provide new therapeutic targets, according to researchers ...
Genetics 5 hours ago | 5 / 5 (1) | 0 |
Can human genes be patented? That was the question posed by Alan J. Snyder, vice president and associate provost for research and graduate studies at Lehigh, and Lee Kaplan, scientific director of cellular and molecular genetics ...
Genetics 13 hours ago | 4 / 5 (1) | 0
Researchers from Queen Mary, University of London have led the largest sequencing study of human disease to date, investigating the genetic basis of six autoimmune diseases.
Genetics May 22, 2013 | 4.5 / 5 (4) | 0 |
University of Minnesota Medical School researchers from the Masonic Cancer Center, University of Minnesota, in partnership with the University's Brain Tumor Program, have developed a new mouse model of malignant peripheral ...
Genetics May 20, 2013 | 5 / 5 (1) | 0 |
Northwestern University scientists have shown a gene involved in neurodegenerative disease also plays a critical role in the proper function of the circadian clock.
Genetics May 16, 2013 | 3 / 5 (1) | 1 |
(Medical Xpress)—A new study by researchers in the US has shown that an ancient virus can be modified to help in the fight against the simian immunodeficiency virus SIV, which is the equivalent in monkeys ...
11 hours ago | 5 / 5 (3) | 0 |
Women at a particular stage in their monthly menstrual cycle may be more vulnerable to some of the psychological side-effects associated with stressful experiences, according to a study from UCL.
8 hours ago | 5 / 5 (2) | 0 |
Biological processes are generally based on events at the molecular and cellular level. To understand what happens in the course of infections, diseases or normal bodily functions, scientists would need to ...
9 hours ago | 5 / 5 (2) | 0 |
Talking on a hands-free device while behind the wheel can lead to a sharp increase in errors that could imperil other drivers on the road, according to new research from the University of Alberta.
5 hours ago | not rated yet | 0
Kate O'Reilly's spring allergy survival kit includes the usual stuff - nasal sprays, allergy pills and a box of tissues. This season, she's added a new weapon to her line of defense: an app on her smartphone.
6 hours ago | not rated yet | 0