Research topics: We are interested in how macrophages kill, how killing is regulated and why killing is not always effective. A medical-biologic perspective guides an effort to understand host defense and microbial resistance at genetic and biochemical levels and to put key hypotheses to the test of experimental interventions in cell culture, mice and sometimes clinical trials. Work on cytokines, the respiratory burst and inducible nitric oxide synthase (iNOS) over 40 years has evolved into the current projects, which involve macrophage interactions with Mycobacterium tuberculosis (Mtb), including the enzymes of Mtb that help the organism resist sterilization by the immune system, and a search for compounds that inhibit those enzymes.
Lab Organization: Each student and postdoc has her or his own project(s). At the same time, the emphasis is on sharing within an interdisciplinary group whose members enjoy teaching and learning from each other. Lab members bring expertise in immunology, biochemistry, chemistry, pharmacology, molecular biology and microbiology. We collaborate extensively with Sabine Ehrt, Dirk Schnappinger, Kyu Rhee, Kohta Saito and Laura Kirkman at Weill Cornell, Michael Glickman at SKI, and Jeremy Rock and Jean-Laurent Casanova at Rockefeller. Each week, most of these labs join for a combined lab meeting. Our lab meets weekly as well. Our lab also participates in a shared weekly journal club, as well as in Departmental, Graduate School and Tri-Institutional activities and national and international collaborations.
Past contributions: This lab has helped to shape our basic understanding of innate immunity and host-pathogen interactions. Original contributions include: that macrophage activation can be brought about by soluble proteins released by host cells (cytokines); that there also exists a cytokine-mediated process of macrophage deactivation (including what is now sometimes called "alternative activation"); that interferon-gamma (IFN-gamma) is the major macrophage activating factor; that transforming growth factor-beta (TGF-beta) and interleukin 10 are major macrophage deactivating factors (observations later extended to lymphocyte deactivation involving T-regulatory cells); that tumor necrosis factor-alpha (TNF-alpha) is a powerful transcription-independent secretagogue for neutrophils; that cell behavior in the immune system is often controlled by binary signals from adhesion receptors (such as integrins) and cytokine receptors; that two of the major antimicrobial and antitumor effector systems of the innate immune system are the production of reactive oxygen intermediates (ROI) and reactive nitrogen intermediates (RNI), a line of research that included identification, purification, characterization, cloning and knockout of inducible nitric oxide synthase (iNOS); and that pathogens and tumor cells express genes with previously unrecognized capacities to confer resistance to ROI and RNI, including, in Mycobacterium tuberculosis, genes encoding peroxynitrite reductase/peroxidase, the proteasome and the Uvr DNA repair pathway. Clinical studies included the demonstration that IFN-gamma activates macrophages in humans, which represented the first use of a cytokine to treat a non-viral infectious disease in man (leprosy).
