Malarial parasite study identifies genes associated with drug resistance
Although widespread use of antimalarial drugs during the past 60 years has selected for drug-resistant strains, dihydroartemisinin (DHA) and piperaquine (PQ) are still effective against parasitic strains on several continents.
Of the 8 antimalarial drugs now available, 7 were used in this study. Chloroquine (CQ) and sulfadoxine-pyrimethamine have lost their effectiveness in most areas; other drugs evaluated were mefloquine, quinine, DHA, amodiaquine, and PQ.
"Based on our data, a combination of [DHA] and [PQ] would be a good [combination therapy]," said senior author Xinzhuan Su, PhD, head of the Malaria Genomics Section, Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, in his email to Medscape Infectious Diseases. He noted that a Chinese team has already employed this therapy.
However, "We definitely need to develop new drugs because the parasites can always overcome the drugs we have and become resistant," Dr. Su added. "We also need to search for drugs that can block transmission, killing sexual and liver stages."
The new study, published online January 31 in Nature Genetics, analyzed 189 culture-adapted P falciparum strains: 146 from Thailand and Cambodia, 26 from Africa, 14 from the Americas, and 3 from Papua New Guinea. Genetic tests revealed heterogeneity that reflected geographic origins, with clusters from America, Africa, and Asia, and distinctive genetic profiles of Thai-Cambodian cultures collected within a radius of approximately 50 km.
Clustering in Cambodia a Surprise
"The clustering of the Cambodian parasites into 2 populations was a surprise because generally parasites from 1 location are very similar. There are 2 potential explanations," said Dr. Su. "One is that 1 'population' was introduced from another place (country) recently. When the Vietnamese army invaded Cambodia in the '70s, they may have introduced some parasites. We have to compare the Cambodian parasites with parasites from Vietnam in order to get some answers. The second possibility is 1 population was derived from drug selection somewhere in Cambodia and spread to the place we sampled."
The researchers developed recombination maps for all 14 chromosomes of P falciparum, finding relatively more recombination on the smaller chromosomes. Locations of recombination "hot spots" or "cold spots" (areas of high or low recombination activity) seemed to be consistent across populations. Among regions with very high levels of recombination were the end of chromosome 1 and a region of chromosome 7 — the latter contains pfcrt, a gene that encodes the P falciparum CQ resistance transporter.
"In malaria, many of the genomic regions where there appeared to be hot spots of recombination were places where there were gene families that are clustered and known to be highly variable antigens," explained senior author Philip Awadalla, PhD, from the Department of Pediatrics, University of Montreal, Faculty of Medicine, Sainte Justine Research Centre, Montreal, Quebec, Canada.
"Gene families can facilitate recombination through unequal crossing-over," Dr. Awadalla told Medscape Infectious Diseases in an email. "And recombination may be selected [for] because it generates variation in antigens." Antigen switching is a characteristic "strategy" of P falciparum and enables the parasite to evade the host's immune response.
The investigators also ran multiple genomewide association studies to identify loci associated with drug responses of the parasites. Parasites of all strains displayed sensitivity to PQ and DHA; in contrast, among 143 Thai-Cambodian P falciparum strains, only 2 were sensitive to CQ, and 6 to sulfadoxine-pyrimethamine. Of the genes associated with antimalarial drug responses, only 3 had minor allele frequencies greater than 15%: pfcrt (whose association with CQ resistance was noted above), pfmdr1 (associated with quinine response), and pfsurfin (no drug associations were known previously).
Seminal Study
"This seminal study provides the first comprehensive genomewide association study of P falciparum parasite populations and their relationship to drug response," commented David Fidock, PhD, associate professor of microbiology and immunology and of medicine (infectious diseases), Columbia University Medical Center, New York City, to Medscape Infectious Diseases via email. "This information will help unravel mechanisms of drug resistance and identify molecules that are evolving in response to either drug or immune pressure," he said.
Dr. Awadalla added, "It tells us something about the regions of the genome that have already been associated with drug resistance. In some cases, they may have already been rapidly evolving regions of the genome. It also suggests," he pointed out, "that it may be more reasonable to develop drug targets for proteins encoded by more slowly evolving regions."
By Jacquelyn K. Beals
Dr. Awadalla, Dr. Su, and Dr. Fidock have disclosed no relevant financial relationships.
Nat Genet. Published online January 31, 2010.
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