BS, Stanford University PhD, University of California at Berkeley   Departmental Award for Outstanding Graduate Student Instructor, UC Berkeley NIH Cancer Research Training Award Postdoctoral Fellowship   Cellular and protein engineering, gene therapy, synthetic systems biology, cancer immunology

We seek to understand interactions between the immune system and pathogens  (including both infectious agents and cancer cells), and develop new tools for modulating these interactions for therapeutic benefit. In particular, we target the mechanisms by which microorganisms and tumors remodel the immune system to evade clearance during chronic diseases.

To maintain health, our immune systems possess multiple mechanisms for striking a fine balance between reactivity against potential threats and tolerance against healthy self tissues. Tumors and pathogens co-opt these mechanisms to establish immunosuppressive microenvironments comprising multiple cell types, signaling molecules, and regulatory mechanisms. These environments must therefore be treated as complex interconnected networks, and understanding them will require a quantitative, systems-level approach.

We are developing novel genetic and biochemical tools (based in gene therapy, protein engineering, and synthetic biology) for “reprogramming” these systems with the goals of (1) safely, specifically, and efficiently reversing immune suppression and (2) tailoring the overall immune response to fit the disease targeted. We are especially interested in engineering new functions into cells of the innate immune system, such as dendritic cells, which play a central role in detecting pathogens and determining the overall nature of the immune response. Such approaches will utilize the Toll-like Receptors (TLRs), a family of biosensor proteins that detect specific pathogen-associated molecules (chemical signatures of infection) and initiate potent immune responses. We will also use quantitative computational modeling to study how key intracellular signaling cascades (signal processing) and cues from the extracellular environmental (secreted molecules, intercellular interactions) contribute to the formation and maintenance of immunosuppressive networks. These models will be used to generate and evaluate strategies for intervention. Related goals include developing new in vitro models for studying these phenomena at a level of molecular detail not currently available. These technologies would be especially useful for applications including “smart” vaccines and the treatment of metastatic cancers.

Selected Publications

Leonard JN, Ghirlando R, Askins J, Bell JK, Margulies DH, Davies DR, Segal DM. (2008) The TLR3 signaling complex forms by cooperative receptor dimerization. PNAS 105, 258-63.

Liu L, Botos I, Wang Y, Leonard JN, Shiloach J, Segal DM, Davies DR. (2008) Structural basis of toll-like receptor 3 signaling with double-stranded RNA. Science 320, 379-81.

Leonard JN, Bell JK, Segal DM. Predicting TLR structures and characterizing ligand binding. Methods in Molecular Biology. (in press)

Leonard JN, Shah P, Burnett JC, Schaffer DV. HIV evades RNA interference directed at TAR by an indirect compensatory mechanism. Cell Host and Microbe. (in press)

Leonard JN, Ferstl P, Delgado A, Schaffer DV. (2007). Enhanced preparation of adeno-associated viral vectors by using high hydrostatic pressure to selectively inactivate helper adenovirus. Biotechnology and Bioengineering 97, 1170-9.

Leonard JN and Schaffer DV. (2006). Antiviral RNAi Therapy: Emerging Approaches for Hitting a Moving Target. Gene Therapy 13, 532-40.

Leonard JN and Schaffer DV. (2005). Computational Design of Antiviral RNA Interference Strategies that Resist Human Immunodeficiency Virus Escape. Journal of Virology 79, 1645-1654.  

Prof. Joshua N. Leonard
Department of Chemical and Biological Engineering
Northwestern University
2145 Sheridan Road Evanston, IL 60208-3120

tel: 847/491-7455
fax: 847/491-3728
E-mail Professor Leonard