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Entamoeba histolytica causes amoebic dysentery and is endemic in many developing countries. This pathogen causes an estimated 50 million cases of amoebic dysentery and 100,000 deaths each year, and thus the socio-economic impact is substantial. The overall goal of my research is to provide a better understanding of energy metabolism in E. histolytica. This microbe is a scavenger that lacks mitochondria as well as many common metabolic pathways, and glycolytic breakdown of glucose has long been thought to be the primary pathway for ATP production. However, E. histolytica colonizes the large intestine during infection, an environment in which glucose is very limited. My lab is working to determine how E. histolytica adjusts its metabolism to adapt to and thrive in this environment. We are using genetic, genomic, and biochemical approaches to identify other pathways and mechanisms used for adaptation and growth in the low glucose environment encountered during infection. The results of these studies are expected to fill a key gap in our knowledge of Entamoeba metabolism during colonization.
Kinetoplastid parasites cause a number of diseases that affect more than 70 people annually. Among this family are Trypanosoma brucei, Trypanosoma cruzi and Leishmania spp, which cause human African trypanosomiasis, Chagas disease, and visceral, cutaneous and mucocutaneous leishmaniasis, respectively. There are no vaccines against these diseases and the current treatments are toxic and difficult to administer, making the search for new drug targets essential. In the search for new therapeutics we investigate essential parasite-specific processes, with the belief that understanding these processes will enable us to specifically target the parasite during treatments while leaving the host relatively unaffected. Kinetoplastid parasites harbor unique organelles, glycosomes, which are essential to parasite survival. The pathways that regulate glycosome biology are rich with potential drug targets. We use a number of biochemical and cell biology approaches to elucidate the mechanisms involved in glycosome biogenesis, maturation, maintenance and remodeling.
Parasites that have developmental stages in distinct hosts encounter remarkably different environments during their lifecycles. For example, parasite members of the family Trypanosomatidae, including the African and American trypanosomes and Leishmainia spp., have required lifecycle stages in both insect vector and mammalian host. These parasites have evolved distinct mechanisms to avoid eradication by the host immune system. In common, however, is the requirement that these parasites must be able to identify the host in which they reside and respond accordingly. The African trypanosome, Trypanosoma brucei, responds to changes in environmental glucose availability to regulate developmental progression. Our group is interested in elucidating the molecular mechanisms employed by the African trypanosome to detect glucose availability, with a particular focus on identifying unique components for targeting for therapeutics. Rationale: The parasitic members of the family Trypanosomatidae infect ~32 million people worldwide. The lack of effective therapies for these maladies emphasizes the need for the identification of new targets for drug development. Our research focuses on identifying for the development of therapies the mechanisms that the African trypanosome uses to “sense” its environment and make developmental decisions.
Trypanosomes are single-celled eukaryotes that comprise both free-living and pathogenic species. We are currently studying three species of trypanosomes that present an array of life histories and host-pathogen interactions: Trypanosoma brucei, a mammalian pathogen transmitted by Tsetse flies that causes African Sleeping Sickness, Crithidia fasciculata, a mosquito pathogen, and Bodo saltans, a free-living trypanosome. My lab is interested in how trypanosomes modulate the metabolism of a key nutrient class, fatty acids, in response to its environment and during progression through its life cycle. Fatty acids are not only an important structural component of membranes and a source of energy, but in the case of T. brucei at least, they also are implicated in immune evasion.
Relatively little is known about fatty acid metabolism in these evolutionarily ancient eukaryotes. Indeed, what we have learned about fatty acid synthesis in these organisms suggest that trypanosome fatty acid metabolic pathways may be quite diverged from higher eukaryotes, and therefore may be valuable for the identification of potential new drug targets for Trypanosome diseases, for improving our understanding of how basic metabolic processes have developed and evolved over time, and may contribute to a better understanding of these pathways as they function in mammals.
Microbial pathogens utilize a variety of strategies to facilitate survival in the infected host. One of the most important mechanisms is the ability to respond to stress and adapt to an adverse host environment. Therefore, inhibiting stress response pathways constitutes a promising antimicrobial therapy. I study a human fungal pathogen Cryptococcus neoformans to understand the mechanistic cellular processes used by pathogenic microorganisms to allow survival in the infected host. C. neoformans is a major opportunistic fungal pathogen worldwide and a leading cause of morbidity and mortality in AIDS patients. In addition, the sibling species, Cryptococcus gattii is responsible for the recent outbreak of fungal-caused meningitis in the Pacific north-west of the U.S. Our work with C. neoformans has led us to hypothesize that this pathogen has evolved unique pathways to control cell division in a manner that allows it to survive within a human host. Testing this hypothesis would provide insights into how eukaryotic pathogens adapt to the host environment and could potentially reveal new targets for therapeutic interventions. In addition, our research will lead to an improved understanding of the evolutionary events that have resulted in alternative mechanisms of mitosis. My research program has the following three main aims: 1. Explore molecular basis for stress-induced changes in ploidy in C. neoformans, 2. Explain the intriguing interconnection between cytokinesis, endocytosis, and stress response in C. neoformans, 3. Elucidate the function of septins, filament forming GTPases, in stress response and pathogenicity of C. neoformans.