Thomas L. Leto, Ph.D.

Senior Investigator

Dr. Leto received his Ph.D. in biochemistry from the University of Virginia for studies on mechanisms of cell membrane assembly. He followed this work with postdoctoral studies at Yale University on membrane cytoskeleton interactions. Dr. Leto joined NIAID in 1988 and became a senior investigator in the Laboratory of Host Defenses in 1996.

Description of Research Program

The research conducted in this section is focused on the body’s capabilities of producing reactive oxygen species (ROS) and the roles of ROS in innate anti-microbial and inflammatory processes. This program originated with interests in the NADPH oxidase of phagocytes (phox system), the importance of which is evident in chronic granulomatous disease where inherited defects in ROS production render patients susceptible to bacteria, fungal infections, and dysregulated inflammatory responses. Early work in this program identified phox genes affected in chronic granulomatous disease and characterized oxidase functional domains and signaling intermediates involved in its assembly and activation.

Renox expression in mouse kidney.

Current efforts are focused on homologous Nox family NADPH oxidases that produce ROS in a variety of tissues. ROS production by these enzymes is thought to serve diverse functions, including hormone and extracellular matrix biosynthesis, oxygen sensing, and cellular signaling involved in processes including apoptosis, cell senescence, and cellular responses to growth factors, hormones, or immune cytokines. Growing evidence suggests several of these novel oxidases also function in host defense and inflammatory responses, as they demonstrate high expression in epithelial cells, appear to be aimed toward the external environment, and support the activity of anti-microbial peroxidases on mucosal surfaces.

Nox family oxidases with potential host defense and inflammatory roles include hydrogen peroxide-generating dual oxidases (Duox1 and Duox2) detected in airways, exocrine glands, and the gastrointestinal tract and oxidases of the colon, kidney, and Nox1 and Nox4 vascular cells. Several novel oxidases are induced or activated by pro-inflammatory cytokines or by host recognition of pathogen-associated microbial patterns.

This group uses a variety of experimental approaches to explore mechanisms of deliberate ROS production and the biological and pathological consequences of this activity, ranging from studies in genetically-modified animal models or tissue and cell culture systems to work on protein structure-function relationships involved in regulated assembly and activation of ROS generators. Ongoing projects include the following:

• Characterization of the Nox1-based multi-component oxidase similar to the phagocytic system that is responsive to receptor activation and involves the Rac1 GTPase
• Elucidation of mechanisms of subcellular targeting and ROS generation by Duox isozymes
• Investigations of responses of Duox and Nox4 to microbial infection
• Studies on the targets of ROS involved in redox-based cellular signaling

Research Group Members

Balazs Rada, Ph.D., Stanislas Morand, Ph.D., Howard Boudreau, Ph.D., Jaeyul Kwon, Ph.D., Agnieszka Korzeniowska, M.S.

Selected Recent Publications

To view a complete listing, visit PubMed.

Choi H, Leto TL, Hunyady L, Catt KJ, Bae YS, Rhee SG. Mechanism of angiotensin II-induced superoxide production in cells reconstituted with angiotensin type 1 receptor and components of NADPH oxidase. J Biol Chem. 2008 Jan 4;283(1):255-67.

Ueyama T, Geiszt M, Leto TL. Involvement of Rac1 in activation of multi-component Nox1- and Nox3-based NADPH oxidases. Mol Cell Biol. 2006 Mar;26(6):2160-74.

Leto TL, Geiszt M. Role of the Nox family NADPH oxidases in host defense. Antioxid Redox Signal. 2006 Sep-Oct;8(9-10):1549-61.

Ueyama T, Lekstrom K, Tsujibe S, Saito N, Leto TL. Subcellular localization and function of alternatively spliced Noxo1 isoforms. Free Radic Biol Med. 2007 Jan 15;42(2):180-90.

Geiszt M, Lekstrom K, Witta J, Leto TL. Proteins homologous to p47phox and p67phox support superoxide production by NADPH oxidase 1 in colon epithelial cells. J Biol Chem. 2003 May 30;278(22):20006-12.

Geiszt M, Witta J, Baffi J, Lekstrom K Leto TL. Dual oxidases represent novel hydrogen peroxide sources supporting mucosal surface host defense. FASEB J. 2003 Aug;17(11):1502-4.

Special Interest Groups: Cell Biology, Structural Biology, Free Radical/Oxygen Club

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