Stephen Vella is a Ph.D. trainee in Silvia Moreno’s laboratory. He is originally from Indiana where he received his B.S. in microbiology at Indiana University. In his first year at UGA, he was awarded an Excellence in Graduate Recruitment Award and a Provost’s Scholars of Excellence Award Fellowship. He has also been awarded an Outstanding Poster Presentation at the Molecular Parasitology Meeting in 2016. And in 2017, he was awarded a T32 fellowship from CTEGD.
NIH T32 Trainee Karla M. Márquez Nogueras is in her 4th year of graduate training in Silvia Moreno‘s laboratory. Before entering the Ph.D. program at UGA, she taught for a semester at Turabo University in Puerto Rico, teaching undergraduate courses like Introduction to Microbiology and Human Anatomy. She has a Bachelor’s degree in Industrial Microbiology and a Master’s in Science where she focused on generating renewable energy systems using methane generated by anaerobic microbial communities.
Karla’s research focus
Karla’s project focuses on calcium signaling in Toxoplasma gondii. Calcium is a universal signal molecule and very little is known about calcium signaling in T. gondii, even considering that all steps of the parasite’s lytic cycle are regulated by calcium. Calcium is highly regulated by Toxoplasma, specially upon exit from host cells and the surrounding calcium changes from very low levels inside the host cell to the high concentration found in the extracellular environment. In order to shed light into the mechanisms involved and to discover the molecules involved they are studying two key aspects: the calcium channels that could be responsible for calcium entry into the cytosol and the calcium binding proteins that could regulate them.
“When I first entered grad school my research goals were different,” said Karla. “During my rotation in Dr. Moreno’s lab, I became fascinated by the biology of Toxoplasma and by how little is known about calcium signaling in T. gondii. As a scientist, I became very curious and interested in finding more about these signaling pathways and I decided to change my research focus.”
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.
“I was invited to the University of Puerto Rico to present my research project and discuss graduate and fellowship opportunities available at UGA. I would be presenting at an undergraduate event organized by the University.”
In addition, she would like to visit the laboratory of Dr. Ivana Kuo at Northwestern University to study the function of two TRP channels that Karla is characterizing. Dr. Kuo uses lipid layers and regular patch-clamp to characterize intracellular and plasma membrane channels. Using this system Karla hopes to understand the physiology of these channels that are important for calcium signaling in T. gondii.
T32 Fellowship helps trainees achieve their goals
“The fellowship will provide me with the necessary experience and opportunities for me to develop the skills to become a better scientist.”
Karla would like to go back to Puerto Rico and establish her own research lab. She would like to have the opportunity to train and give students the same opportunities that were given to her during her Ph.D. training.
“All the skills gained throughout this two years will prepare me for my ultimate goal which is to have my own research lab.”
Msano Mandalasi, a post-doctoral trainee in Chris West‘s laboratory, is originally from Malawi, (located in southeastern Africa) and obtained her bachelor’s degree in Chemistry from the University of Malawi. After graduation, she worked briefly for the University of Malawi and then came to the US to obtain a Master’s degree in Chemistry. Later, she enrolled in a doctoral graduate program at the University of Maryland Eastern Shore where she graduated in 2012. She spent two years teaching undergraduate Chemistry before deciding to get back into research. She joined Dr. West’s group while he was at the University of Oklahoma and moved with the lab to the University of Georgia.
Msano’s research focus
The focus of Msano’s project is on the role of prolyl hydroxylation and glycosylation of E3 Ubiquitin ligase on Toxoplasma growth.
With a research background mostly in chemistry and biochemistry, her graduate research introduced her to some aspect of parasitology working on Schistosome glycobiology. However, she did not have a strong background in molecular biology prior to joining the West lab. This current project merges glycobiology and molecular biology and also extends some parasitology studies, thus giving her the opportunity to learn molecular biology and parasitology to complement her chemistry background. A combination of this expert knowledge will benefit her to address the research objectives on her Toxoplasma project.
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. Msano plans to use her capstone experience to give oral presentations at scientific meetings, to publish some of the studies conducted within this time period, and interact with other trainees in the program.
T32 fellowship helps trainees achieve their goals
“Through the funding provided by the T32 Training Grant, I will be able to address research questions that should lead to launching my own area of research,” said Msano.
Msano hopes to run her own independent research program in academia one day.
Support trainees like Msano Mandalasi by giving to the Center for Tropical & Emerging Global Diseases
Silvia Moreno and her research team at the University of Georgia’s Center for Tropical & Emerging Global Diseases and Department of Cellular Biology provided evidence that it is possible to develop a drug combination that acts synergistically by inhibiting host and parasite enzymes in a recently published article in Antimicrobial Agents and Chemotherapy.
What is toxoplasmosis?
Toxoplasmosis is caused by the pervasive intracellular Apicomplexan parasite Toxoplasma gondii. The parasite is found throughout the world and can infect humans and a number of animal species. In the U.S., people may contract it by consuming undercooked meats, especially pork, lamb, venison, or through contact with contaminated cat feces.
Human infections are usually asymptomatic but the parasite can persist in the form of tissue cysts. It has been estimated that 30–50% of the global population may be chronically infected with Toxoplasma. The immune system of a healthy individual can control the infection, but it can reactivate when there is immunosuppression due to organ transplant, cancer chemotherapy, or in people infected with HIV.
Toxoplasmosis is especially dangerous to the unborn fetus when the mother becomes infected during pregnancy as it can result in miscarriage or stillbirth. Surviving infants can suffer from visual, hearing, motor, cognitive, and other problems.
Some strains of T. gondii can cause severe ocular disease in people with a healthy immune system. Current drug therapies do not prevent disease progression that leads to blindness in ocular toxoplasmosis patients.
Toxoplasmosis represents a serious public health problem and no preventative or therapeutic vaccine is available for humans.
Need for better drug treatments for toxoplasmosis
Drugs presently used against toxoplasmosis do not eradicate chronic infection and as many as half of treated patients do not respond to the therapy. Additionally, a large number of people have an allergic reaction to the current treatment option. Furthermore, some the current drugs have recently become very expensive.
There is a need for safe and effective treatment.
Moreno and her team study the isoprenoid pathway to identify new drug targets. Isoprenoids are lipid compounds with many important functions. One particular step in this pathway has been identified as essential in T. gondii. A drug targeting this pathway could kill the parasite.
Drug combination may provide more effective and less expensive treatment
Moreno’s group proposes a double hit strategy of combining inhibitors of host and parasite pathways as a novel approach against toxoplasmosis. They have found a synergistic effect by combining new and potent sulfur-containing bisphosphonates, as well as other commercially available bisphosphonates, with several statins against a lethal infection of T. gondii using a virulence mouse model.
Bisphosphonates are widely used for the treatment of bone disorders. Previous studies by Moreno and her colleagues have shown that bisphosphonates inhibit the growth of a variety of protozoan parasites like T. gondii. There are a number of commercially available bisphosphonate drugs.
Statins are a class of drugs typically prescribed to lower cholesterol. They work by blocking a particular enzyme known as 3-hydroxy-methylglutaryl-coenzyme A reductase. As with the bisphosphonates, there are already a number of commercially available statins.
Bisphosphonates alone have been very effective when treating a lethal infection of T. gondii in mice. However, Moreno’s team found that combining bisphosphonates with the statin atorvastatin (Lipitor) was almost 3 times more effective under similar conditions of infection and treatment. Additionally, they found very low doses of both drugs could be used for treatment, which would significantly decrease the potential for adverse side effects.
This double hit strategy may be the key to effective treatment because the parasite not only makes its own isoprenoids, but it can also import them from the host. The ability to manipulate the host cell for its own benefit poses a challenge for drug development against toxoplasmosis. Therefore, inhibiting the host from producing this material along with inhibiting the parasite’s ability to create isoprenoids is an interesting and novel strategy for drug development.
Further studies for this novel therapeutic approach needed
This study demonstrates that early treatment is key to the cure of infection with a particular strain of T. gondii for acute infection. Since current treatments often fail to cure chronic infection Moreno and her group will next test this combination strategy in an established chronic infection mouse model.
Furthermore, Moreno predicts that this double-hit strategy of inhibiting both host and parasite pathways will work for other intracellular Apicomplexan parasites, such as the malaria-causing Plasmodium parasite. Additional studies will be needed to test this hypothesis.
An online version of this study is available: Li Z-H, Li C, Szajnman SH, Rodriguez JB, Moreno SNJ. 2017. Synergistic activity between statins and bisphosphonates against acute experimental toxoplasmosis. Antimicrob Agents Chemother 61:e02628-16. https://doi.org/10.1128/AAC.02628-16