Rick Tarleton Archives - Page 4 of 4 - Center for Tropical and Emerging Global Diseases

Protozoan persister-like cells and drug treatment failure

Donna Huber on August 23, 2019

Antimicrobial treatment failure threatens our ability to control infections. In addition to antimicrobial resistance, treatment failures are increasingly understood to derive from cells that survive drug treatment without selection of genetically heritable mutations. Parasitic protozoa, such as Plasmodium species that cause malaria, Toxoplasma gondii and kinetoplastid protozoa, including Trypanosoma cruzi and Leishmaniaspp., cause millions of deaths globally. These organisms can evolve drug resistance and they also exhibit phenotypic diversity, including the formation of quiescent or dormant forms that contribute to the establishment of long-term infections that are refractory to drug treatment, which we refer to as ‘persister-like cells’. In this Review, we discuss protozoan persister-like cells that have been linked to persistent infections and discuss their impact on therapeutic outcomes following drug treatment.

Michael P. Barrett, Dennis E. Kyle, L. David Sibley, Joshua B. Radke & Rick L. Tarleton. Nat Rev Microbiol. 2019 Aug 23. doi: 10.1038/s41579-019-0238-x.

New method patented to provide increased vaccine efficacy

Donna Huber on November 13, 2018

Rick Tarleton

by Donna Huber

Vaccines can be an efficient and cost-effective method of preventing and treating pathogen-induced illnesses. As new pathogens appear and old pathogens re-emerge, improved vaccines are needed. For one emerging global disease, Chagas Disease, effective vaccine development has long been elusive. Now, Rick Tarleton, Regents’ Professor in the department of cellular biology, and former graduate student Sam Kurup have received a patent for a vaccine method that improves efficacy. Even more promising, it can be used to develop vaccines for a variety of pathogens.

Chagas Disease, caused by the parasite Trypanosoma cruzi and spread by blood-feeding insects commonly known as “kissing bugs”, is endemic to the Americas, including the U.S. The infection can result in irreparable damage to the heart and digestive system, and in Central and South America, it kills more than 50,000 people each year.

Tarleton and Kurup found that vaccines consisting of parasites that have been genetically modified to produce stronger pathogen-associated molecular patterns, or PAMPs, increase the immune response of the host. PAMPs are molecules associated with the pathogen that are recognized by the immune system. T. cruzi does not naturally produce strong PAMPs.

In mice vaccinated with transgenic T. cruzi expressing potent bacterial PAMPs, they saw a superior immune response and a more rapid and persistently stronger acquired immune response. Furthermore, in chronically infected mice, they also saw a boost in immune response and a reduction in parasite load. This is good news as presently available treatments are not completely effective and often have severe side effects.

The inability of classical adjuvants to induce innate immunity and to generate a long-lasting T-cell response in T. cruzi infection has been a hurdle in the development of T-cell-based vaccines. Using PAMPs-modified attenuated vaccines may be an ingredient for preventing and treating this and other pathogenic illnesses.

Highly competent, non-exhausted CD8+ T cells continue to tightly control pathogen load throughout chronic Trypanosoma cruzi infection

Donna Huber on November 12, 2018

Abstract

Trypanosoma cruzi infection is characterized by chronic parasitism of non-lymphoid tissues and is rarely eliminated despite potent adaptive immune responses. This failure to cure has frequently been attributed to a loss or impairment of anti-T. cruzi T cell responses over time, analogous to the T cell dysfunction described for other persistent infections. In this study, we have evaluated the role of CD8⁺ T cells during chronic T. cruzi infection (>100 dpi), with a focus on sites of pathogen persistence. Consistent with repetitive antigen exposure during chronic infection, parasite-specific CD8⁺ T cells from multiple organs expressed high levels of KLRG1, but exhibit a preferential accumulation of CD69⁺ cells in skeletal muscle, indicating recent antigen encounter in a niche for T. cruzi persistence. A significant proportion of CD8⁺ T cells in the muscle also produced IFNγ, TNFα and granzyme B in situ, an indication of their detection of and functional response to T. cruzi in vivo. CD8⁺ T cell function was crucial for the control of parasite burden during chronic infection as exacerbation of parasite load was observed upon depletion of this population. Attempts to improve T cell function by blocking PD-1 or IL-10, potential negative regulators of T cells, failed to increase IFNγ and TNFα production or to enhance T. cruzi clearance. These results highlight the capacity of the CD8⁺ T cell population to retain essential in vivo function despite chronic antigen stimulation and support a model in which CD8⁺ T cell dysfunction plays a negligible role in the ability of Trypanosoma cruzi to persist in mice.

Angela D. Pack, Matthew H. Collins, Charles S. Rosenberg, Rick L. Tarleton. 2018. PLOS Pathogens. https://doi.org/10.1371/journal.ppat.1007410

Study reveals key cause of treatment failure in Chagas disease

Donna Huber on March 29, 2018

Researchers at the University of Georgia have discovered that dormancy of the parasite Trypanosoma cruzi prevents effective drug treatment for Chagas disease, which kills more than 50,000 people each year in Central and South America and is a growing threat in the United States and Europe.

The disease infects an estimated 6 million to 7 million people, according to the World Health Organization, although some scientists estimate the number could be as high as 20 million. Chagas disease causing irreparable damage to the heart and digestive system, and effective prevention and treatment methods are virtually nonexistent.

Proliferating Tdtomato expressing Trypanosoma cruzi amastigotes dilute the violet dye staining while non-replicating dormant parasite in the same host cell retains the violet signal.

In a new study published in eLife, Rick Tarleton and his research team at the Center for Tropical and Emerging Global Diseases sought to determine why drug treatments such as benzimidazole frequently fail.

“Benzimidazole has been shown to be particularly effective in reducing parasite infection,” said Tarleton, Regents’ Professor in the department of cellular biology. “A single dose can eliminate nearly 90 percent of parasites within 48 hours, but we didn’t know why it didn’t kill 100 percent of the parasites.”

For the first time, they show that a small proportion of T. cruzi parasites halt replication within 24 hours of invading the host cell. These dormant parasites are resistant to extended drug treatment and can resume replication after treatment ends, thus re-establishing a growing infection.

The researchers don’t know why some of the parasites exhibit this behavior, but they are hopeful that future studies into this mechanism will shed more light on the way T. cruzi evades the host’s immune response.

“This isn’t drug resistance in the classical way we think of resistance,” said Tarleton. “The parasites aren’t dormant because of the presence of the drug.”

In fact, while treatment continued they saw some of the dormant parasites “wake up” and then become susceptible to the treatment. The team believes the key to effective treatment will be to catch the parasite as they resume replication, continuing medication until no parasites remain in the host.

“This discovery really offers a solution for current drugs to be used in a more effective way,” said Tarleton. “A longer, less concentrated dosing schedule could lead to a cure.”

T. cruzi lifecycle — Life cycle of Trypanosoma cruzi, the cause of Chagas disease (graphic by Lindsay Robinson

An online version of the study is available: https://elifesciences.org/articles/34039

Trainee Spotlight: Molly Bunkofse

Donna Huber on January 4, 2018

NIH T32 trainee Molly Bunkofse, a Ph.D. student in Rick Tarleton‘s laboratory, is originally from Illinois and I obtained my BA in Biology from a small, liberal arts college called Augustana, which is located in Rock Island, IL.

Molly’s research focus

Molly’s project focuses on the host CD8+ T cell response that is generated against flagellar proteins from the parasite Trypanosoma cruzi and exploring how these responses might be enhanced.

“I chose this research focus because I have always been interested in the host immune response to pathogens and especially pathogens that are able to escape the immune response and persist, such is the case in T. cruzi infection.”

Trainee capstone experience

Each T32 trainee is provided with the opportunity to complete a capstone experience at the end of their fellowship. This experience allows for an extended visit to a collaborator’s laboratory or travel to a scientific meeting where they present their research and interact with colleagues.

“For my capstone experience, I’d like to work in South America where Chagas disease is endemic, perhaps with one of our collaborators that works with human patients infected with T. cruzi.”

T32 fellowship helps trainees achieve their goals

“I think that the T32 fellowship will provide me with new opportunities to develop my research and skills as a scientist. The experiences and training will enable me to become a well-rounded scientist that can think critically and logically approach a question/problem.”

Molly hopes to continue her research in a government laboratory after graduation.

Cellular biology professor Rick Tarleton named Regents’ Professor at UGA

Donna Huber on March 21, 2017

Rick Tarleton

Athens, Ga. – Rick Tarleton, Distinguished Research Professor and University of georgia Athletic Association Distinguished Professor in Biological Sciences in the Franklin College of Arts and Sciences, has been named Regents’ Professor, effective July 1.

Regents’ Professorships are bestowed by the University System of Georgia’s Board of Regents on faculty members whose scholarship or creative activity is recognized nationally and internationally as innovative and pace-setting.

Tarleton, who is a professor in the department of cellular biology and founder of UGA’s Center for Tropical and Emerging Global Diseases, has made research advances that have the potential to transform the lives of the 10 million to 20 million people suffering from Chagas disease, a potentially deadly parasitic infection that primarily affects people in Central and South America.

“Through the founding of the Center for Tropical and Emerging Global Diseases in 1998, Dr. Tarleton has helped make the University of Georgia a leader in promoting global health,” said Senior Vice President for Academic Affairs and Provost Pamela Whitten. “His research into Chagas disease has implications for millions of people and inspires hope in the fight against one of the world’s most neglected parasitic diseases.”

Tarleton’s laboratory established the Chagas Drug Discovery Consortium, which has brought together international researchers, pharmaceutical companies and not-for-profit groups to improve existing drug protocols and to establish new protocols for Chagas disease. Tarleton’s research has resulted in findings that explained the host-parasite relationship regarding the immune system, and he has continued his research to encompass the development of diagnostics and the evaluation of drugs and vaccines.

“Dr. Tarleton’s superb, innovative research has revolutionized our understanding of Chagas disease and is guiding efforts to translate that scientific revolution into practice both in vaccine production and drug discovery, as well as treatment for the affliction,” Kojo Mensa-Wilmot, professor and head of the department of cellular biology, wrote in a nomination letter.

Tarleton’s work has resulted in five patents and the founding of a proteomics software company known as BioInquire, which was acquired by biotech firm NuSep Holdings, as well as numerous public-private partnerships.

As the founding director of the Center for Tropical and Emerging Global Diseases, Tarleton was instrumental in recruiting additional world-renowned researchers and attracting funding that has enhanced field research in 20 countries. The center has garnered more than $135 million in research funding over the past 15 years and has 24 faculty members from eight units across campus.

“This center has garnered international recognition through Professor Tarleton’s research, as well as his vision and ability to attract key talent to expand the scope of research conducted in CTEGD,” Robert T. Jacobs, vice president of Anacor Pharmaceuticals, wrote in his nomination letter. “The impact of CTEGD goes beyond the science conducted by its researchers, as it has increased the international reputation of the University of Georgia as an important player in the scientific research community.”

In addition to holding the title of Distinguished Research Professor, Tarleton is a recipient of the 2012 Lamar Dodd Award.

The Regents’ Professorship includes a $10,000 salary increase and is granted for an initial period of three years, which may be renewed. No more than one Regents’ Professorship is given in any year at UGA.

For more information about the Regents’ Professorship, see http://provost.uga.edu/index.php/resources/professorships/regents-professorships.

Writer: Camie Williams