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Category: Research Article

UGA researchers develop breakthrough tools in fight against cryptosporidium

Donna Huber on July 15, 2015

Boris StriepenAthens, Ga. – Researchers at the University of Georgia have developed new tools to study and genetically manipulate cryptosporidium, a microscopic parasite that causes the diarrheal disease cryptosporidiosis. Their discoveries, published in the journal Nature, will ultimately help researchers in academia and industry find new treatments and vaccines for cryptosporidium, which is a major cause of disease and death in children under 2 years old.

Crypto, as researchers often call it, is most commonly spread through tainted drinking or recreational water. When a person drinks contaminated water, parasites emerge from spores and invade the lining of the small intestine, causing severe diarrhea. In 1993, more than 400,000 people living in the Milwaukee area were infected with crypto when one of the city’s water treatment systems malfunctioned.

The parasite is especially problematic in areas with limited resources, and recent global studies have shown crypto to be one of the most important causes of life-threatening diarrhea in infants and toddlers. There is currently no vaccine and only one drug—nitazoxanide—approved by the U.S. Food and Drug Administration for cryptosporidiosis, but it provides no benefit for those in gravest danger: malnourished children and immunocompromised patients.

“One of the biggest obstacles with crypto is that it is very difficult to study in the lab, and that has made scientists and funders shy away from studying the parasite,” said Boris Striepen, co-author of the paper and Distinguished Research Professor of Cellular Biology in UGA’s Franklin College of Arts and Sciences. “We think that the techniques reported in this paper will open the doors for discovery in crypto research, and that will, in turn, lead to new and urgently needed therapeutics.”

One of their techniques involves manipulating crypto so that it emits light, making it much easier to detect and follow the parasite. Previously, researchers would have to examine samples under a microscope and count crypto spores one by one, which is both time-consuming and inaccurate.

Now, by simply measuring light, researchers may test thousands of drug candidates simultaneously to see if they have the ability to inhibit crypto growth.

“There are enormous libraries of chemicals available now, and some of these chemicals may work as a treatment for crypto, and this technology will help us find them much more rapidly,” said Striepen, who is also a member of UGA’s Center for Tropical and Emerging Global Diseases.

The team also developed a way to genetically modify the parasite using a technique called CRISPR/Cas9, which allows scientists to make very precise changes to an organism’s genome and observe the effects. By knocking out specific crypto genes, researchers can test their importance for the parasite and make predictions on their potential value as a drug target.

Epidemiological studies have demonstrated that children develop immunity to crypto as they get older, but the mechanisms that provide that immunity are poorly understood. The genetic techniques developed in Striepen’s lab will help identify the foundation of natural immunity, opening the possibility for vaccine development. They may also help to develop weakened parasite strains that can no longer cause disease but still induce lasting immunity.

“Drug treatments are important, but finding a way to prevent the disease in the first place would be the most effective way to deal with an early childhood disease,” said Sumiti Vinayak, lead author of the paper and assistant research scientist in Striepen’s lab.

The team also developed new methods to study the disease in mice. Mouse tests are an important precursor to human drug and vaccine trials, and the ability to study crypto in a living organism will speed discovery and therapeutic development.

“Now that we have overcome these initial hurdles, we have a great opportunity to move forward much faster,” Striepen said. “There is need, there is opportunity and now there is technical ability, so I think we may have reached a turning point in the fight against this important disease.”

Additional authors of the study were Mattie Pawlowic, Adam Sateriale, Carrie Brooks, Caleb Studstill, Yael Bar-Peled and Michael Cipriano, all from UGA. This study was supported financially by the National Institutes of Health under grant numbers R01AI112427 and T32AI060546, the Center for Disease Control and Prevention, the UGA Research Foundation and the Georgia Research Alliance.

The study on “Genetic modification of the diarrhoeal pathogen Cryptosporidium parvum” is available online at www.nature.com/nature/journal/vaop/ncurrent/full/nature14651.html.

Writer: James Hataway
Contact:Boris Striepen

UGA researchers find hormone receptor that allows mosquitoes to reproduce

Donna Huber on April 8, 2015

Mark Brown mosquito
Dr. Mark Brown’s mosquito lab in Athens. September 2010

Athens, Ga. – University of Georgia entomologists have unlocked one of the hormonal mechanisms that allow mosquitoes to produce eggs.

The results provide insight into how reproduction is regulated in female mosquitoes, which transmit agents that cause malaria and other diseases in humans and domestic animals. Their work was published in the April edition of the Proceedings of the National Academy of Sciences.

The model for this research is the yellow fever mosquito, Aedes aegypti. Females have to consume a blood meal before they are able to produce a batch of eggs. The blood meal triggers the mosquito’s brain to release two hormones, an insulin-like peptide known as ILP and an ovary ecdysteroid-ogenic hormone known as OEH, which activate processes in the female mosquito that result in mature eggs.

Many hormones, including OEH and ILP, act through receptors on the surface of cells. In 2008, study co-authors Mark Brown, a professor of entomology, and Michael Strand, a Regent’s Professor, characterized the receptor for ILP in mosquitoes, which helped reveal many details about its role in egg formation. OEH plays an equally important role in female reproduction, but its receptor was more difficult to identify.

“From previous work, we knew that the fruit fly Drosophila melanogaster does not produce OEH. A different group of fruit flies, including Drosophila mojavensis—as well as all mosquitoes we had genomes for—do have OEH,” said the study’s lead author Kevin Vogel, a postdoctoral fellow also in the College of Agricultural and Environmental Sciences’ entomology department.

“Most hormones bind a single receptor, so we hypothesized that an OEH receptor should be found in mosquito genomes as well as Drosophila mojavensis, but not in the genome of Drosophila melanogaster.”

By identifying and comparing the sequences of more than 400 receptors in the genomes of two fruit flies and three mosquito species, they identified a single gene for a receptor with an unknown function within the species distribution they expected.

By targeting the gene encoding the receptor, the authors found that disabling its expression inhibited the mosquitoes’ ability to produce eggs after a blood meal.

“This receptor fills a major gap in our understanding of the regulation of mosquito reproduction,” Strand said. “Going forward, we are well positioned to better characterize the steps leading to egg production and potentially identify points at which we can disrupt reproduction and control mosquito populations.”

The study is available online at www.pnas.org/content/early/2015/04/02/1501814112. Research reported in this release was supported by the National Institutes of Health under grant numbers R01AI033108 to Brown and Strand and F32GM109750 to Vogel.

For more information on the UGA department of entomology, see www.ent.uga.edu.

Writer: J. Merritt Melancon Mark Brown
Contact:Kevin Vogel Michael Strand

UGA researchers discover route for potential Chagas disease animal vaccine

Donna Huber on October 23, 2014

Rick Tarleton

Athens, Ga. – Researchers at the University of Georgia have discovered a new way to direct a vaccine to the parasite that causes Chagas disease, a leading cause of death among young to middle-age adults in areas of South America where it is endemic.

Chagas disease is caused by the parasite Trypanosoma cruzi, which spreads via a subspecies of blood-feeding insects commonly known as “kissing bugs” because they tend to bite people on the face and lips. While the disease can progress slowly, chronic infection almost inevitably results in irreparable damage to heart and digestive system tissues.

“Chagas disease is incredibly understudied, because it is a disease of poverty,” said Rick Tarleton, Distinguished Research Professor in the department of cellular biology in UGA’s Franklin College of Arts and Sciences and co-author of a paper describing their work in Cell Host and Microbe. “I don’t know if we will ever see a Chagas disease vaccine for humans, but our lab is working on a unique vaccine for animals that may ultimately protect people at greatest risk for exposure.”

The paper reported a new vaccine technique that targets antibodies found on T. cruzi’s flagellum, a tail-like appendage similar to those found on sperm cells, which allows the parasite to propel itself through blood as it searches for cells to infect.

Immediately after infection, the flagellum essentially snaps off through a process of cell division. The discarded tail is broken down by the host cell, but it leaves behind a kind of molecular calling card that Tarleton and his co-author, Samarchith Kurup, were able to isolate and use as the foundation for a vaccine.

In laboratory tests, T cells taught to recognize the proteins found on the flagellum were able to detect infected host cells more than 20 hours earlier than is normally observed, suggesting that the immune system became aware of the parasite’s presence very shortly after infection.

“We want to find a way to help the animal’s immune system recognize which cells are infected with the parasite, and the antigens in the flagellum are an attractive target,” Tarleton said. “If we can express these proteins in a vaccine, T cells will go to work and destroy compromised cells before the infection becomes chronic.”

A significant portion of Tarleton’s work in UGA’s Center for Tropical and Emerging Global Diseases has focused on the development of a vaccine that can be administered to domestic animals, which play a major role in Chagas disease transmission throughout much of the Americas.

“The bugs that transmit this disease are found commonly in substandard housing with poor insulation, but the bugs tend to acquire the parasite from the family pet that spends a lot of time outside,” he said. “These are the same bugs that go on to bite people, so if we can prevent animals from acquiring the disease, we can hopefully prevent T. cruzi’s spread into human populations.”

The research team hopes that this latest discovery will become a major component of its vaccine development, which will ultimately target multiple unique signatures created by T. cruzi infection.

“There’s a lot more work to do, but this new target will be very helpful in the fight against Chagas’ disease,” Tarleton said.

For a full version of the paper, see http://www.cell.com/cell-host-microbe/abstract/S1931-3128(14)00336-9

The research discussed in this article was supported by two grants from the National Institutes of Health under project numbers AI108265 and AI108265.

Writer: James Hataway
Contact:Rick Tarleton