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Research Program Description: Research in my laboratory primarily focuses on the human pathogenic fungus Aspergillus fumigatus. This is a ubiquitous environmental mold that can cause a variety of diseases in humans, including a life-threatening invasive infection in the setting of immune compromise. Treatment options exist for invasive aspergillosis, but therapeutic failures are common with mortality rates as high as 85% in some patient populations. This high mortality rate is primarily due to two issues: 1) our inability to diagnose these infections early and 2) a paucity of effective anti-fungal drugs to treat advanced infections. My laboratory is interested in addressing both of these problems. Currently, the main focus of the laboratory is to better understand the process of cell wall synthesis in A. fumigatus. Pathogenicity and survival of A. fumigatus in vivo requires a number of virulence factors, with the ability to generate a rigid cell wall being one of the most important. Targeting cell wall synthesis with anti-fungal therapy has been successful in the treatment of a number of fungal infections. However, identification of additional drug targets in the pathway of cell wall assembly is hindered by our limited knowledge of these synthetic mechanisms. My laboratory is taking two parallel and complementary approaches to identify enzymes/proteins involved in cell wall synthesis. One aim is to develop enzymatic assays for monitoring the activity of glycosyltransferase enzymes likely involved in cell wall synthesis and to use these assays to purify/identify the corresponding proteins. We are also taking forward genetic approaches with the development of mutagenesis and RNA interference libraries in A. fumigatus that will be screened for cell wall defects or with the biochemical assays discussed above. We are also interested in improving fungal diagnostics, with the goal of achieving earlier and more reliable detection of A. fumigatus and other fungal organisms from patient samples. Currently, we are investigating a few novel approaches, both in how we obtain patient specimens and in how we detect fungi in those specimens. Combined, these basic and clinical research projects have the ultimate goal of contributing to the field of medical mycology in such a way as to reduce the morbidity and mortality associated with invasive fungal infections. Selected Publications: Klutts, J.S. and Doering, T.L. "Cryptococcal Xylosyltransferase 1 (Cxt1p) from Cryptococcus neoformans Plays a Direct Role in the Synthesis of Capsule Polysaccharides". J.Biol. Chem. 2008. 283: 14327-34. Klutts JS, Levery SB, Doering TL. A beta-1,2-xylosyltransferase from Cryptococcus neoformans defines a new family of glycosyltransferases. J Biol Chem. 2007 Jun 15;282(24):17890-9. Klutts JS, Yoneda A, Reilly MC, Bose I, Doering TL. Glycosyltransferases and their products: cryptococcal variations on fungal themes. FEMS Yeast Res. 2006 Jun;6(4):499-512. (Review) Klutts JS, Liao RS, Dunne WM Jr, Gronowski AM. Evaluation of a multiplexed bead assay for assessment of Epstein-Barr virus immunologic status. J Clin Microbiol. 2004 Nov;42(11):4996-5000. Griffith CL, Klutts JS, Zhang L, Levery SB, Doering TL. UDP-glucose dehydrogenase plays multiple roles in the biology of the pathogenic fungus Cryptococcus neoformans. J Biol Chem. 2004 Dec 3;279(49):51669-76. Klutts S, Pastuszak I, Edavana VK, Thampi P, Pan YT, Abraham EC, Carroll JD, Elbein AD. Purification, cloning, expression, and properties of mycobacterial trehalose-phosphate phosphatase. J Biol Chem. 2003 Jan 24;278(4):2093-100. Klutts JS, Hatanaka K, Pan YT, Elbein AD. Biosynthesis of d-arabinose in Mycobacterium smegmatis: specific labeling from d-glucose. Arch Biochem Biophys. 2002 Feb 15;398(2):229-39. |
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