Leishmaniasis, trypanosomiasis, and malaria are parasitic diseases that affect more than 500 million individuals worldwide and are major public health problems (Teixeira et al., 2006;Wellems et al., 2009;WHO, 2010). Understanding the basic biology of these parasites is critical for developing methods to control disease. In these pathogenic organisms, a variety of membrane proteins are targeted to the flagellum, where they may serve in sensing the environment (Singla and Reiter, 2006;Bloodgood, 2010). While several proteins that are preferentially targeted to the flagellar membrane have been identified in Leishmania and the related trypanosomes (Piper et al., 1995;Godsel and Engman, 1999;Gull, 2003), how these proteins are targeted to the flagellum and what functions they perform on this sensory organ remain active areas of research. The three Leishmania mexicana glucose transporters offer an ideal system to investigate protein targeting to the flagellar membrane, as only the LmxGT1 isoform is targeted to the flagellum while the LmxGT2/LmxGT3 isoforms are localized to the plasma membrane of the cell body.
The specific aims of this application are to: 1) identify the underlying mechanism that target LmxGT1 to the flagellar membrane, and 2) investigate a potential sensory function for this flagellar glucose transporter by examining the regulation of glucose uptake and chemotaxis behaviors of wild-type and lmxgt1 null-mutants. These studies aim to elucidate a flagellar targeting pathway that likely operates for multiple membrane proteins in Leishmania and related trypanosomes, as well as identify a flagellar specific sensory role for this glucose transporter.
Understanding the basic biology and requirements for survival of parasites can lead to new ways of treating and preventing the spread of parasitic diseases. In many protozoan parasites, specialized membrane proteins are preferentially targeted to the flagella (Nasser and Landfear, 2004;Singla and Reiter, 2006;Bloodgood, 2010);however, not much is known about how these proteins are selectively targeted to this organelle or what functions they serve there. I seek to elucidate how the Glucose Transporter 1, one of the three essential glucose transporters in Leishmania mexicana (Burchmore et al., 2003), is targeted to the flagellar membrane and to investigate a potential sensory function of this protein.
|Rodriguez-Contreras, Dayana; Aslan, Hamide; Feng, Xiuhong et al. (2015) Regulation and biological function of a flagellar glucose transporter in Leishmania mexicana: a potential glucose sensor. FASEB J 29:11-24|
|Landfear, Scott M; Tran, Khoa D; Sanchez, Marco A (2015) Flagellar membrane proteins in kinetoplastid parasites. IUBMB Life 67:668-76|
|Tran, Khoa D; Vieira, Danielle P; Sanchez, Marco A et al. (2015) Kharon1 null mutants of Leishmania mexicana are avirulent in mice and exhibit a cytokinesis defect within macrophages. PLoS One 10:e0134432|
|Tran, Khoa D; Rodriguez-Contreras, Dayana; Vieira, Danielle P et al. (2013) KHARON1 mediates flagellar targeting of a glucose transporter in Leishmania mexicana and is critical for viability of infectious intracellular amastigotes. J Biol Chem 288:22721-33|