The word Apicomplexa may be unfamiliar to most people. But the parasites it describes are all too familiar--causing malaria, toxoplasmosis and several other diseases. These scourges are complex and difficult to study, but a new model system may change that.
In the past, researchers have largely used such traditional lab models as yeast or E. coli bacteria to understand processes in Apicomplexa, and the results have at times been mixed. Many aspects of how Apicomplexa live and cause disease remain poorly understood at the mechanistic level because they only find poor matches in the biology of traditional model organisms.
Now, a team from the University of Georgia and Montana State University has developed a way to conduct powerful genetic studies directly in the parasite using Toxoplasma as a model. The team developed methods to generate large numbers of mutant parasites with defective growth and tools to identify the genes carrying the mutation. This type of study, often dubbed "forward genetics," allows scientists to discover novel genes behind essential biological processes.
"Using this new approach, we have genetically dissected the way the parasite divides and multiplies within its host cell," said UGA cellular biologist Boris Striepen of the Center for Tropical and Emerging Global Diseases. "Importantly, this approach should be broadly applicable, allowing unbiased genetic analysis of any part of parasite biology for which a screen can be devised using this model."
"Protozoans causing malaria and other serious diseases affect millions of people across the planet," said White of the department of veterinary molecular biology at Montana State University.
"These are clever parasites that grow inside our own cells, and the more they grow, the greater damage they cause. What we have done in the work published in the PLoS paper is open the door to the critical genes that these parasites must express in order to grow. These are the 'Achilles heels' of this pathogen family. Many of the genes are unique and could give us valuable leads on how we might stop parasite growth and prevent disease."
The specific organism used in the study was Toxoplasma gondii, a parasitic protozoan whose main host is the cat but which can be carried in most warm-blooded animals. Twenty percent of the U.S. population is chronically infected with this pathogen but infection is usually benign; however, severe disease can occur in people with a suppressed immune system, such as those with HIV/AIDS or in pregnant women. T. gondii has also proven to be a good study model because it has clearly defined microscopic structures, is easy to culture and manipulate and is in general better understood than other Apicomplexa.
Understanding how these parasites work is important because they infect a wide variety of vertebrate and invertebrate animals and occupy a unique intracellular niche that allows them ready access to nutrients while sheltering them from the immune system. The paper published in PLoS Pathogens* describes a genetic analysis of the apicomplexan cell division machinery in T. gondii, but it has far greater implications.
In fact, the new system should provide important clues for other Apicomplexa, such as Plasmodium, the organism that causes malaria, a disease that infects hundreds of millions of people a year and kills between one and three million, most of them children in Sub-Saharan Africa.
Developing new drugs for these diseases is problematical since the Apicomplexa are eukaryotes and have many of the same metabolic pathways as their animal hosts, including humans. This means many drugs that might be used to kill or damage the parasites will also harm their hosts. A deeper understanding of how Apicomplexa work at the cellular level is essential to uncover differences that can be exploited as targets for drugs and vaccines.
So learning more about the parasites and their "flexible cell cycle" has enormous human and animal health implications.
*The research was published February 15 in the journal Public Library of Science Pathogens. Co-corresponding author on the paper is Michael White of Montana State University. Other authors on the paper include, from the University of Georgia, Marc-Jan Gubbels, Mani Muthalagi, Carrie Brooks and Ben Parrot; from Boston College, Thomasz Szatanek and Jayme Flynn; and from Montana State University, Margaret Lehmann, Maria Jerome and Josh Radke.
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