Generic selectors
Exact matches only
Search in title
Search in content
Post Type Selectors

Tag: Cryptosporidium

A Genetically Tractable, Natural Mouse Model of Cryptosporidiosis Offers Insights into Host Protective Immunity

Cryptosporidium is a leading cause of diarrheal disease and an important contributor to early childhood mortality, malnutrition, and growth faltering. Older children in high endemicity regions appear resistant to infection, while previously unexposed adults remain susceptible. Experimental studies in humans and animals support the development of disease resistance, but we do not understand the mechanisms that underlie protective immunity to Cryptosporidium. Here, we derive an in vivo model of Cryptosporidium infection in immunocompetent C57BL/6 mice by isolating parasites from naturally infected wild mice. Similar to human cryptosporidiosis, this infection causes intestinal pathology, and interferon-γ controls early infection while T cells are critical for clearance. Importantly, mice that controlled a live infection were resistant to secondary challenge and vaccination with attenuated parasites provided protection equal to live infection. Both parasite and host are genetically tractable and this in vivo model will facilitate mechanistic investigation and rational vaccine design.

Adam Sateriale, Jan Šlapeta, Rodrigo Baptista, Julie B. Engiles, Jodi A. Gullicksrud, Gillian T. Herbert, Carrie F. Brooks, Emily M. Kugler, Jessica C. Kissinger, Christopher A. Hunter, Boris Striepen. Cell Host Microbe. 2019 Jun 18. pii: S1931-3128 (19) 30251-3. doi: 10.1016/j.chom.2019.05.006.

UGA researchers report milestone in global fight against a major cause of diarrheal disease

Sumiti Vinayak and Boris Striepen
Assistant research scientist Sumiti Vinayak, left, and Distinguished Research Professor Boris Striepen work together in Striepen’s lab in the Coverdell Center for Biomedical and Health Sciences. Striepen and Vinayak are working together on vaccine and drug research for cryptosporidiosis, a disease caused by cryptosporidium, a microscopic parasite commonly spread through tainted drinking or recreational water, and it is a major cause of diarrheal disease and mortality in young children around the world. Credit: Andrew Davis Tucker, University of Georgia

 

Athens, Ga. – Infectious disease scientists from research institutions including the University of Georgia have reported the discovery and early validation of a drug that shows promise for treating cryptosporidiosis, a diarrheal disease that is a major cause of child mortality and for which there is no vaccine or effective treatment.

“Cryptosporidiosis is largely a disease of poverty,” said Boris Striepen, Distinguished Research Professor of Cellular Biology in UGA’s Franklin College of Arts and Sciences and a member of the Center for Tropical and Emerging Global Diseases. “Globally, it primarily affects infants in developing countries, but there are patients in the U.S.-those with weakened immune systems, such as HIV/AIDS or transplant patients-that would benefit greatly from new therapeutics.”

Striepen began studying crypto, as researchers often call the parasite that causes cryptosporidiosis, more than a decade ago. Now he and Sumiti Vinayak, assistant research scientist at UGA’s Center for Tropical and Emerging Global Diseases, along with scientists at Novartis and Washington State University, have reported the discovery of KDU731, a potent inhibitor of cryptosporidium, in the journal Nature.

Identifying KDU731 as a potential drug for the treatment of cryptosporidiosis began with the screening of a selection of 6,200 compounds that showed strong activity against the related malaria parasite. The Novartis team led by Ujjini H. Manjunatha and Thierry T. Diagana identified compounds with activity against crypto and found KDU731 particularly promising based on preclinical data.

Using a new mouse model, UGA’s Striepen and Vinayak showed that oral treatment with the drug dramatically reduced intestinal infection of immunocompromised mice. Additional research, led by Jennifer A. Zambriski at Washington State University, showed that treatment with KDU731 also leads to rapid resolution of diarrhea and dehydration in neonatal calves, a clinical model of cryptosporidiosis that closely resembles human infection.

Crypto is most commonly spread through tainted drinking or recreational water. When a person drinks contaminated water, parasites emerge from spores and invade the cells that line the small intestine, causing severe diarrhea that can last for up to three weeks.

In 1993, more than 400,000 people living in the Milwaukee, Wisconsin, area were infected and became ill when one of the city’s water treatment systems malfunctioned. More than 100 people, mostly AIDS patients, died during the outbreak.

Outbreaks have also been linked to swimming pools and water parks. Crypto is the most common cause of diarrheal illness and outbreaks linked to recreational water because it is not easily killed by chlorine and can survive up to 10 days in properly treated water.

The Centers for Disease Control and Prevention reported at least 32 outbreaks in U.S. facilities during 2016-twice as many as in 2014, according to preliminary data in the agency’s May 18 Morbidity and Mortality Weekly Report.

Recent global studies have shown crypto to be one of the most important causes of life-threatening diarrhea in infants and toddlers, especially in areas that lack access to clean water. There is no vaccine and only one drug, nitazoxanide, approved by the U.S. Food and Drug Administration, but it provides no benefit for those in gravest danger-malnourished infants and immunocompromised patients.

Crypto is notoriously difficult to work with in a laboratory setting, but Striepen has developed new genetic techniques that make it easier to detect and follow the parasite. One technique involves manipulating crypto so that it emits light and is easier to detect and measure. For this study, Striepen’s team engineered a new “reporter” parasite that is amenable to whole-animal imaging, allowing the researchers to non-invasively track and record dissipation of the infection during treatment.

Striepen’s genetically modified organisms have been made available to researchers across the world in the hope that more scientists will be drawn to studying crypto.

“This is an important problem,” he said. “No one institution can solve it alone. It needs significant investment, and it needs a lot of people with good ideas.”

“The discovery of this compound represents an important step toward urgently needed treatment for gravely ill children around the world,” said Thierry Diagana, head of the Novartis Institutes for Tropical Diseases.

An online version of the study is available at http://dx.doi.org/10.1038/nature22337.

 

Writer: Allyson Mann
Contact:Boris Striepen Sumiti Vinayak

UGA researcher receives $1 million for cryptosporidium research

Boris Striepen

Athens, Ga. – Researchers at the University of Georgia have received $1 million from the Wellcome Trust and the Bill & Melinda Gates Foundation to speed the development of new drugs for the treatment of cryptosporidiosis, a major cause of diarrheal disease and mortality in young children around the world.

Cryptosporidiosis is caused by cryptosporidium, a microscopic parasite commonly spread through tainted drinking or recreational water. There is currently no vaccine and only a single drug of modest efficacy available to treat cryptosporidiosis.

“Cryptosporidiosis is a tremendous public health challenge,” said Boris Striepen, Distinguished Research Professor in Cellular Biology in the Franklin College of Arts and Sciences and a member of UGA’s Center for Tropical and Emerging Global Diseases. “We are extremely grateful to the Trust and the Foundation for providing generous support and leadership to drive a global research agenda to face this challenge.”

Cryptosporidium is notoriously difficult to study in the laboratory, and this has stalled the development of better treatments. But earlier this year, Striepen and his research group created new tools to genetically manipulate the parasite, and his team will use funds from the Wellcome Trust and Gates Foundation to leverage this new technology and speed drug discovery.

The Wellcome Trust’s Pathfinder Award of $244,000 will support a collaboration between UGA and the Novartis Institute for Tropical Diseases, a public-private partnership between the pharmaceutical company Novartis and the Singapore Economic Development Board.

The Novartis Institute for Tropical Diseases “has been at the forefront of discovery of new treatments for malaria, tuberculosis and sleeping sickness,” Striepen said. “Engaging a group with this track record to the problem of cryptosporidiosis will be game changing.”

The primary goal of the joint project is to develop better assays to evaluate the effectiveness of drugs in cell cultures and mice. These assays will be used to discover novel candidate drugs using the Novartis Institute for Tropical Diseases’ large collection of candidates.

A $775,000 grant from the Bill & Melinda Gates Foundation will support the development of genetic technology to discover specific drug targets within the parasite, which will ultimately help enhance drug potency and reduce side effects.

Initially, the project will validate targets for drugs for which predictions for likely candidates can be made from prior experience-in particular from the related malaria parasite. In a second phase the project will discover the yet unknown targets of novel drugs.

“The need for effective treatment of cryptosporidiosis is critical, both nationally and internationally. This highly welcome initiative is a major step for those millions of children who globally suffer from this devastating disease,” said Dan Colley, director of CTEGD and former director of the CDC’s Division of Parasitic Diseases.

For more information on the UGA Center for Tropical and Emerging Global Diseases, visit http://ctegd.uga.edu/.

The Wellcome Trust is a global charitable foundation dedicated to improving health. For more information, visit www.wellcome.ac.uk.

Writer: Donna Huber
Contact:Boris Striepen

UGA researchers develop breakthrough tools in fight against cryptosporidium

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