Study in 'Science' IDs clues to better treat parasitic infection
By Joe Carey and Will Sansom
SAN ANTONIO (Nov. 21, 2013) — Scientists from The University of Texas Health Science Center at San Antonio and Texas Biomedical Research Institute (Texas Biomed) have successfully identified the mutations that result in drug resistance in a parasite infecting more than 200 million people worldwide. Their detailed understanding of the drugs' mechanism of action raises prospects for improved therapies.
“This is a major breakthrough,” said first author Claudia Valentim, Ph.D., a UT Health Science Center graduate who is now a postdoctoral fellow at Ohio State University. “We were able to identify the critical gene by crossing resistant and sensitive worms in the laboratory and then analyzing the genomes of the progeny. This method is commonly used for fruit flies and other laboratory organisms, but has not previously been possible for schistosome parasites.”
The new study was funded by the National Institutes of Health, the World Health Organization, the Wellcome Trust and the Robert A. Welch Foundation, and appears in the Nov. 21 online edition of the journal Science.
Second in deaths to malaria
Adult schistosome parasites are half an inch long and live in the human blood vessels, laying thousands of eggs, many of which become lodged in the liver or bladder wall, causing portal hypertension, liver failure and bladder cancer. “We don’t know the death toll from these parasites” says the UT Health Science Center’s Philip LoVerde, Ph.D., “but our best estimates are that more than 200,000 people die annually from this infection in Africa alone, making this parasitic disease second only to malaria in terms of mortality.”
There is no vaccine for schistosomiasis, so this disease is controlled using drug treatment, which must be repeated periodically because people become reinfected through contact with water where the intermediate snail hosts live. The problem is that there are very few effective drugs available. The drug Oxamniquine, the subject of this research, kills just one of the three species of schistosome parasite that infect humans. The research raises hope that this drug can be redesigned to kill the two major schistosome species responsible for 99 percent of schistosomiasis cases worldwide.
Prospects for a more effective treatment
John Hart, Ph.D., a collaborator on this study from the UT Health Science Center, explains: “By using X-ray crystallography and computational methods we were able to precisely pinpoint how the drug interacts with the critical protein in one schistosome species, and to identify the key differences in this protein in the related parasite species. With some targeted chemical modification, we think it will be possible to make a drug that kills both major schistosome species. This is what we are working on now.”
There is only one drug currently available for treating schistosomiasis and resistance has been reported, so new drugs are urgently needed.
“This really shows the utility of genome sequencing,” says Tim Anderson, Ph.D., a Texas Biomed geneticist, who is a corresponding author on the paper along with Drs. LoVerde and Hart. “The schistosome genome was sequenced in 2009. Without this, the work would have been painfully slow.”
Researchers involved in international study
Co-authors on the paper were from Britain and Italy, and also included Frédéric Chevalier, Ph.D., and Marcio Almeida, Ph.D., of Texas Biomed and Alex Taylor, Ph.D. and Xiaohang Cao, M.D. of the UT Health Science Center at San Antonio. All Health Science Center collaborators are in the institution’s School of Medicine.
The University of Texas at San Antonio also played an important role, Dr. LoVerde said. “In the future, we will engage the Center for Innovation in Drug Discovery (a collaboration of the UT Health Science Center and UTSA) to take this further. Affected persons keep their infections for 10, 20, even 30 years. Modifying Oxamniquine for use against several species will be life-changing for them.”
The University of Texas Health Science Center at San Antonio, one of the country’s leading health sciences universities, ranks in the top 3 percent of all institutions worldwide receiving National Institutes of Health funding. The university’s schools of medicine, nursing, dentistry, health professions and graduate biomedical sciences have produced more than 29,000 graduates. The $765.2 million operating budget supports eight campuses in San Antonio, Laredo, Harlingen and Edinburg. For more information on the many ways “We make lives better®,” visit www.uthscsa.edu.
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