Center for Tropical and Emerging Global Diseases
University of Georgia
Learn more about malaria and current efforts to eliminate this disease from CTEGD faculty member David Peterson. The Athens Science Cafes, sponsored by the Athens Science Alliance, meets at Little Kings Shuffle Club on W. Hancock Ave. The talk will start at 7 pm on Thursday, September 26. Read more in the Athens Science Observer.
The immune system can control a relapsing form of malaria enough to avoid clinical signs of disease, but it doesn’t eliminate transmissible parasites from the body that may still be infectious to mosquitoes. That’s the conclusion of a study on a nonhuman primate model of Plasmodium vivax infection, which has implications relevant to malaria elimination strategies.
Keep reading about the MaPHIC study at Technology.org
Dennis Kyle, director of the Center for Tropical and Emerging Global Diseases, was interviewed during the 4th Annual Amoeba Summit about his work with Naegleria fowleri. Listen to the interview at Outbreak News Today.
Dr. Fernando Sanchez-Valdéz, from Salta, Argentina, completed a Ph.D. in Molecular Biology at the Faculty of Pharmacy and Biochemistry at the University of Buenos Aires, Argentina in 2014. After his Ph.D., he completed a postdoctoral fellowship in Dr. Rick Tarleton´s laboratory at University of Georgia. In 2018, he obtained a Research Scientist position in the career pathway of the National Research Council in Argentina (CONICET). Earlier this year, he was awarded a fellowship from the CTEGD-Janssen Visiting Scholars Program, which enabled him to return to the Tarleton Research Group.
The main focus of my research has been to uncover the mechanism of drug resistance in the Chagas disease agent, Trypanosoma cruzi. The main question we are trying to answer is why the treatment with highly effective drugs like Benznidazole (the current available treatment for Chagas disease) often fails to cure Chagas disease. By combining ex vivo luminescence assays and tissue-clearing techniques we were able to report, for the first time, the presence of dormant non-replicating amastigotes forms in the chronic phase of the disease. Dormant amastigotes were uniquely resistant to extended drug treatment in vivo and in vitro and could re-establish a flourishing infection after treatment interruption. T. cruzi‘s capacity to become dormant makes them transiently drug-resistant, suggesting that this phenomenon accounts for the failure of the otherwise highly active compounds such Benznidazole (Sanchez-Valdéz, et al eLife 2018).
I returned to Athens in February 2019 to continue working on the findings we made during my postdoctoral training in the Tarleton Laboratory. I initially decided to come UGA based on a colleague’s recommendations and the fact that Tarleton´s lab is one of the reference centers for Chagas disease research. It’s a really motivating environment to do science since the scientific and technical level here is really high as well as diverse including areas as immunology, drug discovery, genetic manipulation, genomics, diagnostics, etc. Also the amount of resources available is impressive not only from the lab but also from the Biomedical Microscopy Core, Cytometry Shared Resource Laboratory and the animal facility at UGA.
Currently, we are expanding our knowledge about T. cruzi dormancy and trying to interfere T. cruzi dormancy using new compounds or the conventional drugs but in a different treatment schedule. One of the approaches we are testing now involves the evaluation of drug doses and treatment schemes able to kill dormant parasites. For this purpose, we are optimizing a robust platform to detect low levels of parasites in whole clarified mice organs using light-sheet fluorescent microscopy. This technique will allow us the specific detection of low levels of persistent dormant parasites.
I am so glad about the opportunity to continue working on T. cruzi dormancy with such experienced and renowned scientists and particularly using state-of-the-art microscopy techniques currently unavailable in South America. This experience will definitely have a positive impact on my career development and probably in the Chagas disease research field.
NemaMetric features Dr. Adrian Wolstenholme: https://nemametrix.com/featured-scientist/featured-scientist-adrian-wolstenholme/
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The unassuming mosquito may be smaller than a dime, but it packs a serious punch, killing more people each year than any other animal. And with average temperatures climbing around the globe, different mosquito species are making their way farther north than ever before and bringing their diseases—malaria, West Nile, dengue, and more—along for the ride.
But thanks to recent discoveries at the University of Georgia, it may soon become easier to fend off the swarm.
Regents Professor of Entomology Michael Strand’s lab found that microorganisms, or microbes, in a mosquito’s gut are essential for growth and development. Mosquito larvae spend anywhere from a few days to two weeks developing in pools of water that can be as small as an upside-down bottle cap. Microbes colonize the larvae’s digestive tracts, forming a community of microorganisms that enables the larvae to mature into adult mosquitos.
The implications of the findings could lead to new approaches for mosquito control.
“If you can disrupt their growth cycle, you could control mosquito populations,” Strand says. “Certain combinations of these organisms that exist in the digestive system of the mosquito also affect how well they are able to acquire and transmit disease-causing microorganisms to people.
Understanding how these organisms alter the mosquito’s ability to transmit diseases offers the potential for increasing resistance to certain organisms they can pass on to people.”
From a more basic science perspective, insects provide a more simplified version of a microbiome, the ecological community of microorganisms that call a space home. Researchers often discuss the roles microbiomes, such as that of the human gut, play in an individual’s health, but it’s difficult to sort through the billions of different organisms that can be present. Mosquitoes, and other insects in general, are much less complex, sometimes hosting only several hundreds of microorganisms in their digestive tracts. The smaller number of microbes make it easier for researchers to study.
“In effect, this simplicity reduces the many variables involved,” Strand says. “Some of the rules determining the importance of gut microbes in mosquito development may also have generalizable applications in how similar processes are regulated in larger animals.”
Sting like a Bee
Mosquitoes aren’t the only insects Strand studies.
His interests lie in parasitology, or how parasites interact with the animals they feed from. Parasitic wasps, comprising over a million different species, are the perfect medium to study parasite-host interactions.
Around 100 million years ago, some parasitic wasps were infected by a virus that became part of their genome. Wasps coopted that virus to deliver different types of genes into hosts.
One way wasps accomplish that is by injecting the coopted virus into other insects along with their eggs. The virus then infects the insects’ cells in much the same way as modern medicine’s gene therapies that use viruses to introduce genes into human patients for disease prevention or treatment.
The virus’ genes suppress the host insect’s immune defenses, which would otherwise destroy the foreign eggs. The wasps can then hatch and develop into adults while slowly consuming the host from the inside out.
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Marc-Jan Gubbels received his Ph.D. at the University of Utrecht, the Netherlands, on diagnostics and vaccines for tick-transmitted Theileria and Babesia parasites of cattle. He then came to the CTEDG for a post-doc with Dr. Boris Striepen on Toxoplasma gondii. In 2005, he transitioned into an independent faculty position at Boston College and continued working on Toxoplasma. His lab is using and developing forward, reverse and functional genetic tools using enzymatic as well as fluorescent protein reporter assays in combination with cell sorting and fluorescence microscopy to learn more about the parasite’s cell biology.
Dr. Gubbels will give the following talk at 4:25 pm.
Klemens Engelberg1, Suyog Chavan1, Tyler Bechtel2, Victoria Sánchez-Guzmán1, Allison Drozda1, Eranthie Weerapana2 and Marc-Jan Gubbels1
1Department of Biology, Boston College, Chestnut Hill, MA, 2Department of Chemistry, Boston College, Chestnut Hill, MA
Toxoplasma gondii replicates by an internal budding mechanism producing two daughter parasites per division round. Budding is driven by cortical cytoskeleton assembly and concludes with the actions of the basal complex (BC). Although the BC is reminiscent of the contractile ring in higher eukaryotes, its composition, mechanism and controls differ substantially. To deepen our insights in this unusual cytokinesis apparatus, we dissected its proteomic composition by reciprocal proximity-dependent biotinylation experiments (BioID). This identified numerous undefined proteins, several of which with critical roles in cell division, next to hints at multiple phosphorylation-based controllers. Next, we assembled a protein-protein interaction network using interaction probability predictions, which defined several sub-complexes as well as protein hubs connecting the complexes. Furthermore, temporal resolution across the budding process revealed components uniquely associated with BC initiation, its expansion and, surprisingly, its mature phase, hinting at functions beyond cell division. Serendipitously, some of the BC proteins were also present in the enigmatic apical annuli, which comprise 5-6 donut shaped structures toward the basal end of the cytoskeleton. Assessment of the annuli resolved their architecture and provided hints toward a function in internal budding, thereby highlighting an underappreciated aspect of cell division.
More information about the Molecular Parasitology & Vector Biology Symposium and the schedule of presentions are available on our website. The deadline to register for the symposium is April 24.
Macrophages are the major cell type infected by Leishmania parasites and the goal of my research is to define the relationship between Leishmania parasites, macrophages and the vasculature. Throughout my graduate studies and postdoctoral positions, I have dedicated my efforts toward understanding parasite-host interactions. As a graduate student at the University of Georgia carrying out research at the Centers for Disease Control and Prevention under Dr. Patrick Lammie, I was exposed to high caliber basic research in the CTEGD while simultaneously confronted with important public health issues in field settings related to neglected tropical diseases. My predoctoral research focused on the ability of monocytes to modulate lymphatic endothelial cell function and how this interaction contributed to the pathogenesis of human filarial disease. For my first postdoctoral position, I moved to the laboratory of Dr. Fabienne Tacchini-Cottier at the University of Lausanne in Switzerland. In Switzerland I gained experience using the mouse model to study the immunologic mechanisms involved in susceptibility to Leishmania infection. For my second postdoctoral position, I went to the laboratory of Phillip Scott at the University of Pennsylvania, a world-renowned professor and institution in the field of immunoparasitology. My initial project in the Scott lab, addressed the role of M2 macrophages as safe havens during Leishmania infection. For my second project in the Scott lab, I merged the knowledge and experience gained from my predoctoral research studying myeloid cells and vessels in filariasis with the technical experience of my first postdoctoral position to address the roles of innate cells in vivo in leishmaniasis. In the past months, I have transitioned to an Assistant Professor at the University of Arkansas for Medical Sciences (UAMS) where I have joined an elite group of vibrant and enthusiastic scientists with expertise in host-pathogen interactions. At UAMS, I am expanding upon previous studies examining vascular remodeling and the role of the VEGF-A/VEGFR-2 signaling pathway in lymphangiogenesis during Leishmania infection. In the future, I will work in collaboration with Dr. Camila Oliveira in Bahia, Brazil in a new project focusing on vascular remodeling during murine and human Leishmania braziliensis infection. These studies will provide important insights into our current understanding of the role of the vasculature during human disease.
Dr. Weinkoff will give the following talk at 2:45 pm
Tiffany Weinkopff
Department of Microbiology and Immunology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, 72205, USA
Our lab investigates the mechanistic basis for the pathogenesis of disease driven by Leishmania, a protozoal parasite that causes cutaneous lesions. Following infection, lesion severity is often increased by an exaggerated inflammatory response. As a result, the inflammatory response can maintain disease even after the parasite infection has been controlled. Given vascular remodeling contributes to the magnitude of many inflammatory conditions, it is hypothesized that the manipulation of factors promoting angiogenesis or lymphangiogenesis would alter lesion severity in leishmaniasis. Our findings demonstrate that murine Leishmania major infection leads to dramatic changes in vessel morphology, number and permeability. At the peak of infection, VEGF-A and VEGFR-2 expression are upregulated and VEGFR-2 blockade led to a reduction in lymphatic endothelial cell proliferation and simultaneously increased lesion size without altering the parasite burden. We showed VEGF-A/VEGFR-2 signaling promotes lymphangiogenesis to restrict tissue inflammation in leishmaniasis. Given VEGF-A/VEGFR-2 signaling contributes to lesion resolution, we are currently investigating the cellular and molecular mediators driving VEGF-A production. We found that macrophages are the predominant cell type expressing VEGF-A during L. major infection and that parasites can directly induce VEGF-A production by macrophages in vitro. Given Leishmania parasites activate HIF-1α and this transcription factor induces VEGF-A expression, we analyzed the expression of HIF-1α during infection. We showed that macrophages are the major cell type expressing HIF-1α during infection and that parasite-induced VEGF-A production is mediated by HIF activation. We are presently examining VEGF-A expression in mice deficient in HIF signaling specifically in myeloid cells. To date, we have shown that LysMCre ARNTf/f mice express less VEGF-A than LysMCre ARNTf/+ control mice following infection, and we are exploring how decreased myeloid VEGF-A production influences vascular remodeling and lesion resolution in these animals. Altogether, these studies suggest macrophage HIF-dependent VEGF-A production contributes to lymphatic remodeling during L. major infection.
More information about the Molecular Parasitology & Vector Biology Symposium and the schedule of presentions are available on our website. The deadline to register for the symposium is April 24.
James Morris is currently a Professor of Genetics and Biochemistry at Clemson University. He earned his BS at The College of William and Mary in Williamsburg VA in 1990 and an M.S. in Entomology at the University of Georgia in Athens GA in 1992. He completed his Ph.D. in Cellular Biology at the University of Georgia in 1997, characterizing the enzymology of a glycosylphosphatidylinositol phospholipase C from the African trypanosome, Trypanosoma brucei, under the supervision of Dr. Kojo Mensa-Wilmot. Following his Ph.D., Jim moved to Baltimore MD to work in the laboratory of Dr. Paul T. Englund, where he was part of the team that developed the first RNAi-based library for forward genetics in any organism – in this case, the African trypanosome. As part of this work, the team developed the vector pZJM (Jim is the “J”) that is still widely used for silencing genes in the parasite.
In 2003, Jim moved to Clemson University as an Assistant Professor in the Department of Genetics and Biochemistry, where he has remained to date. His team has focused on resolving the mechanisms that protozoan parasites use to sense and metabolize the important sugar glucose during infection of their human host. Through these studies, parasite-specific components of the sugar sensing and uptake pathway have been identified and, in an on-going collaborative effort, small molecule inhibitors of the pathways with anti-parasitic activity have been developed. While his team has historically focused on the African trypanosome, more recent work on the malaria parasite Plasmodium falciparum and the brain-eating amoeba Naegleria fowleri suggests that exploiting the sugar metabolism pathways of these single-celled invaders may also prove useful in the development of new therapeutics.
Dr. Morris will give the following talk at 12:05 pm.
James C. Morris
Eukaryotic Pathogens Innovation Center, Clemson University
Glucose is critical for the infectious blood stages of the African trypanosome, Trypanosoma brucei, serving as both a key metabolic agent and an important signaling molecule. While lack of the hexose is toxic to the proliferative long slender life stage of the parasite, the absence of glucose initiates differentiation in the non-dividing short stumpy (SS) form. These parasites demonstrate hallmarks of development into the next lifecycle stage, the procyclic form (PF) parasite, that include resumption of growth and expression of PF-specific antigens. Both SS differentiation and the growth of the resulting PF parasites is inhibited by glucose and non-metabolizable glucose analogs, with the latter observation suggesting a potential receptor-mediated mechanism for perception of the sugar. The importance of the hexose to the parasite for both metabolic a developmental needs suggests that glucose uptake or distribution inhibitors would be potentially useful anti-parasitic compounds. To identify small molecule inhibitors of glucose acquisition, we developed parasites that endogenously express FRET-based protein glucose sensors in the cytosol or glycosomes. Using these cells, we have completed a 25,000-compound pilot screen and have identified inhibitors with useful medicinal chemistry properties that have potential as a new line of lead compounds against the parasite.
More information about the Molecular Parasitology & Vector Biology Symposium and the schedule of presentions are available on our website. The deadline to register for the symposium is April 24.