Research

Trypanosomes cause human diseases

The trypanosome subspecies Trypanosoma brucei brucei, infective to cattle, is non-infectious to humans and has become our most utilized trypanosome model system. Molecular parasitologists generally find this genetically malleable trypanosome convenient for exploring basic facets of trypanosome molecular biology and biochemistry. This is one of the two trypanosome species we use in our lab. Other T. brucei subspecies, T. brucei rhodesiense and gambiense are the causative agents of African Sleeping Sickness endemic to parts of Africa.
 
Trypanosoma cruzi is the other trypanosome species we study in the lab, and it causes Chagas’ disease, recently reviewed in the New England Journal of Medicine. Heart disease is a common outcome of chronic T. cruzi infection, which is endemic to South and Central America and is also a U.S. concern for our immigrant community. In fact, in December 2015 NPR reported on the U.S. impacts of this disease. T. cruzi has a very different life cycle than T. brucei and for this reason there are topics we specifically want to study in T. cruzi rather than T. brucei. We study multiple strains of T. cruzi which show differences in degree of infectivity and disease progression.
 
Zimmer Lab ResearchTrypanosomes: masters at reinventing themselves
Many parasitic human pathogens are vector transmitted including T. cruzi, T. brucei, and the closely related Leishmania spp. T. cruzi is transmitted by the “kissing bug” and T. brucei by the tsetse fly. The environments of the human and insect hosts differ in temperature, pH, immune defenses, osmolarity, and nutrient availability. Therefore, trypanosomes transition through different life stages at which they are adapted to cope with the unique conditions of that stage (diagrams above and below). Often the same trypanosome species in different life stages appears morphologically very different, and metabolism differs to cope the nutrient availability of the environment. We study the trypanosome gene expression changes that are necessary for survival at different life stages.
 
Zimmer Lab ResearchTrypanosome mitochondrial gene expression is stage-specifically regulated and very different from that of other eukaryotes
Changing metabolic pathways due to changing nutrient accessibility make it likely that changes in metabolic gene expression occur throughout trypanosome life cycles. Many genes of the trypanosome mitochondrial genome encode components of the Electron Transport Chain, and others are required to sustain this important organelle, so much of our work focuses on its gene expression. RNA stability and a unique type of RNA editing are two control points for regulating abundance of mitochondrial gene products.
 
Example projects
One focus of the lab is to understand how and why mitochondrial gene expression changes in T. cruzi as it progresses through its life cycle. We use cell culture, trypanosome cell biology techniques, quantitative RT-PCR, next-generation sequencing, and microscopy to test our hypotheses.
Mammalian cells infected with trypanosomes, between 1 and approx 100 trypanosomes per cell
 
One focus is to better understand the role that a mitochondrial mRNA cis-acting element, 3’ non-encoded tails, plays in all aspects of mitochondrial gene expression. We work in T. brucei and use and both standard molecular techniques and next-generation sequencing approaches to answering these questions.
 
A third focus is to understand the biochemistry and function of the enzymes that degrade RNA – ribonucleases. We are currently characterizing a cytosolic ribonuclease. We have biochemically characterized its in vitro activity, and are now determining its localization and identifying potential substrates.
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