Malaria is an insidious disease, often slipping past our best defenses and killing an estimated 600,000 people a year around the world − 75 percent of whom are children barely five years old.
Stopping the parasite that causes malaria has been the focus of a number of ongoing studies by researchers at the University of South Florida’s College of Public Health (COPH) and Center for Global Health and Inter-Disciplinary Research. A comprehensive new paper sheds light on the unique challenges in how the organism adapted to survive.
“Malaria is still a major global health problem and parasite resistance to the limited available drugs keeps on rising,’’ said Dr. Jenna Oberstaller, research associate with the Adams Lab of the USF Genomics Program, Department of Global, Environmental and Genomics Health Sciences and first corresponding author on the study. “The world desperately needs new antimalarials to keep the disease under control.’’
Oberstaller and her colleagues published their paper, “Supersaturation mutagenesis reveals adaptive rewiring of essential genes among malaria parasites,” in Science, the journal of the American Association for the Advancement of Science, the world’s oldest and largest general science organization.
The study was an international collaboration with USF that included Drs. John Adams, one of study’s senior authors and director of USF’s Center for Global Health and Inter-Disciplinary Research (GHIDR); Thomas Otto, of the University of Glasgow; and Julian Rayner, and his group at the Cambridge Institute for Medical Research. Oberstaller, Rayner and Adams are co-corresponding authors.
The project was funded in part by a grant that provides advanced training for the next generation of scientists that underpins the 100,000 person-strong biomedical work force in Florida.
Conquering malaria is a challenging task in part because it is not a single disease with a single cure. Malaria is caused by two very different types of Plasmodium parasites that require very different approaches to treat and eliminate. The first (and deadliest, especially in Africa) is a single species, P. falciparum.
The other major species is not as lethal but the main cause of malaria everywhere else, including Central and South America, South-East Asia and Oceania and even remains a threat to Florida as discovered only last year. Ideal treatments should work against both types of parasite, but this is not always the case.
“What we’ve done for the first time is pinpoint all the most important genes required for both types of human malaria parasite to survive, which gives researchers a prioritized list of genes as the best likely drug targets that work against both,” Oberstaller noted. “The differences in which genes are essential are also bigger than we thought between both types of parasite, which has implications for malaria treatment specifically and how parasites adapt to their hosts in general.”
The new COPH study follows on the team’s research from 2018 – also published in Science – in which the scientists, for the first time ever, identified the core repertoire of essential genes of P. falciparum – the world’s most deadly parasite.
For the new study, the team used the same tools and applied them to determining all essential genes for the other major group of human malaria parasites, providing “an incredible amount of resolution’’ that might lead to more precise drug-targeting of essential genes.
“We need to know more about how these parasites work so that we can make the smartest choices in which genes to target for effective new treatments,’’ Oberstaller said. Because malaria is caused by a very clever organism that adapts well to treatment, she added, “we need targets informed by parasite biology that are harder to evolve resistance against.’’
Saturation mutagenesis is a technique where researchers thoroughly mutate all the organism’s genes one at a time, then monitor the effect on the organism − here, a deadly mosquito-borne parasite. If the parasite dies from the mutation, the gene was essential for survival (and therefore might be a good drug target).
“Supersaturation mutagenesis means we made so many mutations in the parasite that not only could we determine all essential genes, we could also identify the smaller regions within genes that are essential,’’ Oberstaller explained. “This is a completely new level of detail that could guide precision drug development against those essential genes.
The study is important because the spread of parasite resistance to current front-line antimalarial drugs continues to be a threat. This growing drug resistance means that while treatments are being used with success in most areas of the world, their effectiveness in the long-term is at risk – underscoring the need for novel drugs to be developed.
“Identifying the conserved essential genes among the most deadly malaria parasites is an important contribution to the war against malaria,’’ Adams said. “The granular details revealed in this study provides new insights in developing better antimalarial therapies. More broadly, our unexpected discovery about the genetics of parasite evolution provides fundamental insight for all biologists’ on how species evolve.’’
The malaria parasite’s exceptional ability to adapt to its environment is another major challenge for elimination. Its complex evolutionary history predates the origins of primates and their many other host species. The variety of Plasmodium have highly conserved gene content despite vast biological differences, and their metabolic processes rely on and adapt to nutrients available from their hosts.
“An unexpected finding from our study was that even though both types of human malaria parasite share most of the same genes, but remarkably those genes were not essential in both,’’ the authors noted. “Even when the same types of processes were critical in both, the underlying genes driving those processes were not − meaning they rewired their metabolism to use the same genes differently. That rewiring is an important part of how the parasite adapts to its host.”
Malaria is not endemic in the United States, meaning it doesn’t regularly occur or spread within the country. However, about 2,000 cases of malaria are imported from other countries every year, according to WHO. That could change with a warming climate and the migration of vectors − mosquitos – to new locations. The problem also could dramatically increase in warmer, wetter southern states.
“We have the right climate and the right mosquitos for transmission, especially here in Florida,’’ Oberstaller said. “Our subtropical location here in Florida also means we’re at the front line for potential incursions of tropical disease, and it’s in our best interests to be vigilant and ready. There is no magical barrier at the U.S. border preventing resurgence.’’
Along with Oberstaller and Adams, the USF team included: Research Associates Dr. Shulin Xu (co-lead author with Oberstaller and Cambridge post-doc Dr. Deboki Naskar), Drs. Justin Gibbons and Camilla Valente Pires; Research Assistant Professor Dr. Chengqi Wang; and Research Scientist Dr. Min Zhang.