My laboratory is interested in the molecular and biochemical basis of parasitic diseases. We are currently studying African trypanosomes which are important protozoan parasites causing human African sleeping sickness and Nagana in cattle. We have made important contributions to the understanding the biology of these parasites and have investigated the underlying mechanisms and function of gene expression, RNA editing, human innate immunity to trypanosome infection and the role of membrane nanotubes and extracellular vesicles (EVs) in communication between trypanosomes and with host cells. Research in the Hajduk laboratory has been funded by NIH, WHO and the Burroughs Wellcome Fund. RNA Editing. Mitochondrial mRNAs in trypanosomes are often modified post-transcriptionally by the insertion or deletion of uridines. This process, termed RNA editing, results in the precise addition of hundreds of uridines at specific sites in the mRNAs creating functional open reading frames. We discovered that alternative editing of mRNAs creates novel open reading frames and protein products. Our current focus is the development of in vivo molecular tools to explore the function of proteins encoded by alternately edited mRNAs (Ochenreiter et al., 2008; Szempruch et al., 2015). Human Innate Immunity. Innate immunity can play an important role in preventing or limiting the effects of a parasitic infection. We are particularly interested in the biochemical and molecular basis for human innate immune killing of African trypanosomes. Trypanosoma brucei brucei is the causative agent of a bovine disease Nagana, and is killed by a toxic subspecies of human specific high-density lipoproteins (HDL). The human sleeping sickness parasites, T. b. gambiense and T .b. rhodesiense have evolved mechanisms of resistance against this trypanosome lytic factor (TLF). Our studies mainly focus on the biochemical mechanism of trypanosome killing as well as the mechanisms of human infectivity by the human sleeping sickness trypanosomes (Kieft et al., 2010; Harrington et al., 2012; DeJesus et al., 2013; Styer and Hajduk, 2015). Nanotubes and Extracellular Vesicles. In 2015, we discovered that African trypanosomes use membrane nanotubes and extracellular vesicles to communicate with each other and to influence the host environment. Membrane nanotubes form by budding of the flagellar membrane resulting in long (10-20mm) extensions from the posterior end of the cell. Membrane nanotubes release extracellular vesicles of a defined proteome carrying several virulence factors. Released extracellular vesicles can fuse with trypanosomes and host cells altering trypanosome infectivity and causing host anemia (Szempruch et al., 2016). The discovery of membrane nanotube and extracellular vesicles raised interesting possibilities for development of therapies that would treat infection-induced anemia and address unresolved questions concerning organ tropism and pathology. Selected Publications (from 134 total) RNA Editing/Moonlighting Mitochondrial Proteins 1. Ochsenreiter, T., Anderson, S., Wood Z.A. and Hajduk S.L. (2008) Alternative RNA editing produces a novel protein involved in mitochondrial DNA maintenance in trypanosomes. Molec. Cell. Biol. 28, 5595-604. (Cover article) PMID: 18606780. 2. Sykes S.E. and Hajduk S.L. (2013) Dual functions of α-ketoglutarate dehydrogenase E2 in the krebs cycle and mitochondrial DNA inheritance in Trypanosoma brucei. Eukaryot. Cell 12:78-90. PMID: 23125353 3. Sykes, S.E., Szempruch, A., and Hajduk, S.L. (2015) The Krebs cycle enzyme -ketoglutarate decarboxylase is an essential glycosomal protein in bloodstream African trypanosomes. Eukaryot. Cell 14, 206-215 (Cover article) 4. Szempruch, A.J., Choudhury, R., Wang, Z., and Hajduk, S.L. (2015) In vivo analysis of trypanosome mitochondrial RNA function by artificial site-specific RNA endonuclase mediated knockdown. RNA 21, 1781-1789. PMID: 26264591 Human Innate Immunity Against African Trypanosomes 1. Kieft, R., Capewell, P., Turner, M., MacLeod, A., and Hajduk, S.L. (2010) Reduced Expression of the Haptoblobin/Hemoglobin Receptor Results in Resistance to Human Innate Immunity in Trypanosoma brucei gambiense. Proc. Natl. Acad. Sci. USA 107, 16137-16141. PMID: 20805508. 2. Stephens, N. and Hajduk, S.L. (2011) Endosomal localization of a GPI-anchored protein in African trypanosomes confers human infectivity. Eukaryotic Cell 10, 1023-1033. PMID:21705681 3. Harrington, J.M., Scelsi, C., Hartel, A., Jones, N.G., Engstler, M., Capewell, P., Macleod, A., and Hajduk, S. (2012) Novel African trypanocidal agents: membrane rigidifying peptides. PLoS One. 7:e44384 PMID: 22970207 4. DeJesus, E., Kieft, R., Albright, B., and Hajduk, S.L. (2013) A single amino acid substitution in the Trypanosoma brucei gambiense haptoglobin-hemoglobin receptor abolishes TLF-1 binding. PLoS Pathogens 9, e1003317. PMID: 23637606. 5. Harrington, J.M., Nishanova, T., Pena, S., Scelsi, C.L., Widener, J. and Hajduk, S.L. (2014) A retained secretory signal peptide mediates HDL assembly and function of haptoglobin related protein. J. Biol. Chem. 289, 24800-24820. PMID: 25037218. 6. Styer, A., and Hajduk, S.L. (2015) Trypanosome lytic factor initiates peroxide induced osmotic lysis of Trypanosoma brucei. J. Biol. Chem. December 8 [Epub ahead of print] PMID: 26645690 7. Hajduk, S.L., Kieft, R., Styer, A., Szempruch, A.J. and Harrington, J.M. (2016) Five questions about Trypanosome Lytic Factor. PLoS Path (Invited review) Trypanosome Membranes and Extracellular Vesicles 1. Szempruch A.J., Dennison L.W., Sykes S.E., Kieft R., Becker A.C., Gartrell A., Martin W.J., Nakayasu E.S., Almeida I.C., Hajduk S.L. and J.M. Harrington. (2016) Extracellular vesicles from Trypanosoma brucei mediate virulence factor transfer and cause host anemia. Cell 164, 246-257. PMID:26771494. 2. Szempruch A.J. and Hajduk, S.L. (2016) Tissue tropism in human infections by African trypanosomes. BioEssays (invited review). The Hajduk Lab Following postdoctoral training at Johns Hopkins Medical School in the laboratory of Dr. Paul Englund, the Hajduk lab was established in 1983 in the Department of Biochemistry and Molecular Genetics at the University of Alabama at Birmingham School of Medicine. In 2002, the lab moved to the Marine Biology Laboratory at Woods Hole MA to establish a program in Global Infectious Disease with funding from the Ellison Medical Foundation. In 2006, the Hajduk lab re-located yet again now to the Department of Biochemistry and Molecular Biology in Athens GA. Over the past three decades the Hajduk Lab trained a number of exceptional scientist who have gone on to make important contributions in research and teaching. The Hajduk Lab has also benefited from exceptional collaborators including Jeff Esko (UCSD), Jay Bangs (University of Buffalo), Annette Macleod (Glasgow University), Ron Orlando (UGA), Lance Wells (UGA), Torsten Ochsenreiter (University of Bern), Igor Almeida (University of Texas, El Paso), and Zefeng Wang (University of North Carolina, Chapel Hill). All of the studies in the Hajduk Lab have been funded by grants from the NIH, NIH, WHO and the Burroughs Wellcome Fund. Current Lab Members Hajduk, Stephen, PI (UGA) Kieft, Rudo, Research Professional (UGA) Gartrell, Anzio, Research Technician (UGA) Styer, Amy, BMB Graduate Student (UGA) Szempruch, Tony, BMB Graduate Student (UGA) Dennison, Lauren, BMB Undergraduate (UGA) Walter, Zachary, BMB Undergraduate (UGA) Harrington, John, Collaborator (Merial U.S) MacLeod, Annette, Collaborator (Glasgow University, UK) Ochsenreiter, Torsten, Collaborator (University of Bern, Switzerland) Almeida, Igor, Collaborator (University of Texas, El Paso) Lance Wells, Collaborator (UGA)
