Researcher receives $5.2 million to develop affordable diagnostic test for Chagas disease
Athens, Ga. – An international team of researchers led by infectious disease experts at the University of Georgia has received $5.2 million from the National Institutes of Health to develop a more accurate, affordable diagnostic test for Chagas disease, a parasitic infection that kills more than 50,000 people each year in Central and South America.
Caused by the parasite Trypanosoma cruzi and spread by blood-feeding insects commonly known as “kissing bugs,” Chagas disease is considered by many to be the most neglected of the neglected tropical diseases. While it is endemic to Latin America, Chagas disease is a growing threat in the U.S. and Europe.
Currently, there are only two drug treatments available; however, their usage is limited due to severe adverse reactions and the length of treatment required.
“Fortunately, there are a number of new drug discovery efforts in Chagas disease. But a major limitation is the difficulty in comparing the relative efficacy of current drugs to newly developed ones,” said Rick Tarleton, UGA Athletic Association Distinguished Research Professor of Biological Sciences in the department of cellular biology and Center for Tropical and Emerging Global Diseases. “One simply can’t wait for 10 years (as current protocols require) to determine if a new drug is better than the existing ones.”
In Chagas disease, the number of parasites in chronically infected individuals is extremely low, making detection of parasites an unreliable test to determine if an individual is infected. Instead, the researchers have focused on the body’s response to infection by measuring the unique antibodies that the immune system creates in response to exposure to T. cruzi.
Tarleton and his UGA colleagues have already developed a successful multiplex blood test that measures antibodies to multiple T. cruzi proteins. While their test has proven to be useful in the laboratory, it is also expensive.
The primary goal of their current project is to make the test more sensitive by expanding the number of T. cruzi antibodies it can detect. But the researchers are also developing techniques to make the test more affordable so that it can be used in diagnostic centers in endemic countries.
“By monitoring a broader range of immune responses, we can achieve a rapid and reliable detection of changes in these responses after treatment. And moving from the current bead-based assay to an array platform makes the reagents and the detector for reading the assay much more affordable,” said Tarleton.
The “gold standard” for determining a cure is for a patient to convert from seropositive to seronegative, meaning that a blood test does not detect any T. cruzi antibodies. The conventional blood test requires a minimum of 24 months to show a decline in antibody response, and complete conversion to a negative blood test can take up to 10 years.
Over the past 12 year, the Tarleton laboratory and CONICET research scientist Susana Laucella’s laboratory in Argentina have shown antibodies tested by the multiplex method are potential surrogate indicators of treatment success. They believe this method will detect significant decline in antibody levels in less than 12 months.
In an effort to more rapidly determine treatment success, the project will also investigate additional potential markers of patients being cured, including antibodies to carbohydrate epitopes and changes in numbers of plasmablasts, the cells that secrete antibodies.
“We are looking for the earliest signs of treatment efficacy,” said Tarleton. “As parasite numbers are reduced due to treatment, we expect, based on data from other systems, that one of the first detectable changes will be in the immune cells that are responding to the presence of parasites and producing antibodies, the plasmablasts.”
The researchers will also be exploring the phenomenon of spontaneous cure-a cure in the absence of treatment-as only anecdotal information is currently available.
“The immune response to T. cruzi infection is actually very strong and as a result, spontaneous cure occurs,” said Tarleton. “However the frequency of cure without treatment is not known, nor are methods available that discriminate between those with active, chronic infections and those who have cured.”
Approximately 20 percent of individuals receive mixed results from conventional blood tests for T. cruzi infection. This is a large number of potentially infected people to leave untreated. However, current therapies have such severe side effects doctors often do not prescribe. Additionally, understanding why some individuals can “cure themselves” could lead to new treatments for the disease.
“The key to the success of this project will be the bringing together of basic research findings with great technology and access to patient groups and their samples-some collected over decades. That is what the partners in this work collectively bring to the problem,” said Tarleton.
Tarleton is joined by collaborators at the Blood Systems Research Institute, the University of California, Irvine, Emory University as well as partners in Argentina and Brazil. Their project is supported by the National Institutes of Health under award number R01-AI125738.
UGA Center for Tropical and Emerging Global Diseases
The University of Georgia Center for Tropical and Emerging Global Diseases draws on a strong foundation of parasitology, immunology, cellular and molecular biology, biochemistry and genetics to develop medical and public health interventions for at-risk populations. Established in 1998, the center promotes international biomedical research and educational programs at UGA and throughout Georgia to address the parasitic and other tropical diseases that continue to threaten the health of people throughout the world. For more information, see ctegd.uga.edu.
Writer: Donna Huber
Contact:Rick Tarleton
UGA researchers to develop new treatment for Chagas disease
Athens, Ga. – University of Georgia researchers in collaboration with Anacor Pharmaceuticals have received a $5.3 million grant from the Wellcome Trust to develop a new drug for the treatment of Chagas disease, which they hope will be ready to enter clinical trials by 2016.
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.
Between 10 and 20 million people, mostly in Central and South America, are infected with Trypanosoma cruzi, and Chagas disease kills more people in Latin America than any other infectious disease—including malaria, tuberculosis and HIV. An increasing number of cases are also being documented outside the normal high transmission areas, including in the U.S. and Europe.
“The two drugs commonly used to treat Chagas disease, benznidazole and nifurtimox, require a long course of therapy and have a number of serious side effects,” said Rick Tarleton, UGA Athletic Association Distinguished Research Professor of Biological Sciences in the department of cellular biology in UGA’s Franklin College of Arts and Sciences. “This combined with the fact that many isolates of the parasite are resistant to these existing drugs emphasizes the tremendous need for new treatments.”
Tarleton’s laboratory will work in partnership with Anacor, a biopharmaceutical company focused on discovering, developing and commercializing novel small molecule therapeutics derived from its boron chemistry platform.
Anacor pioneered the development of a boron-based drug class called oxaboroles, which researchers hope will serve as the foundation for a new Chagas therapy.
Boron is a naturally occurring element that is found commonly in fruits, vegetables, milk and coffee, but it is only recently that scientists have begun exploring the potential of boron-containing small molecules in drug development for a variety of infectious agents.
“These new drug classes have a lot of potential for a variety of diseases, including many of the most neglected diseases of humans,” said Tarleton, who is a member of UGA’s Center for Tropical and Emerging Global Diseases. “We have worked with Anacor to identify some potent lead compounds for use in Chagas disease, and this funding will help turn those leads into effective drugs.”
For more information about Anacor, see www.anacor.com.
UGA Center for Tropical and Emerging Global Diseases
The University of Georgia Center for Tropical and Emerging Global Diseases draws on a strong foundation of parasitology, immunology, cellular and molecular biology, biochemistry and genetics to develop medical and public health interventions for at-risk populations. Established in 1998, the center promotes international biomedical research and educational programs at UGA and throughout Georgia to address the parasitic and other tropical diseases that continue to threaten the health of people throughout the world. For more information, see ctegd.uga.edu.
Writer: James Hataway
Contact:Rick Tarleton
UGA researchers discover route for potential Chagas disease animal vaccine
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