Highlights of the lab’s history

Our work has contributed to an integrated immunologic-biochemical picture of how macrophages protect the host from intracellular microbial pathogens and how some microbes persist. This thrust began with Carl Nathan’s research as a medical student and oncology fellow and continued when he led his own group within the Cohn-Steinman lab at Rockefeller University in 1977. The Nathan lab moved to what is now Weill Cornell Medicine in 1986. Within WCM, our lab moved from 1300 York Avenue to the Belfer Research Building in March 2014.

From the late 1960’s through the early 1990’s, we established that lymphocyte products activate macrophage bactericidal pathways and identified two of the major effector mechanisms, the production of large amounts of reactive oxygen species (ROS) and reactive nitrogen species (RNS). We identified interferon-gamma (IFN) as the first macrophage-activating cytokine in vitro and in humans, introduced it into the clinic, and identified transforming growth factor-beta (TGF-β) as the first immunosuppressive cytokine.

Our lab and our collaborators purified, cloned, knocked out and characterized inducible nitric oxide synthase (iNOS) biochemically and functionally, discovered the cofactor role of tetrahydrobiopterin in NOS’s and introduced iNOS as a therapeutic target.

Although iNOS helps the host control Mtb, Mtb resists sterilization by host immunity. Since the mid-1990’s out lab has focused on the biochemical basis of this resistance.

Major research areas and a selection of key papers over the lab’s history are listed below.

 

Macrophage activation and deactivation. Our lab discovered how antigen-stimulated lymphocytes activate macrophages for enhanced antimicrobial effector function by secreting cytokines and identified enhanced respiratory burst capacity as the first biochemically defined effector mechanism of activated macrophages. We identified IFN-γ as the major macrophage activating factor and TGF and IL10 as the first macrophage-deactivating cytokines. We introduced IFNinto the clinic in studies in patients with leprosy.

Nathan, C. F., M. L. Karnovsky, and J. R. David. Alterations of macrophage functions by mediators from lymphocytes. J. Exp. Med. l33: 1356-1376, 1971 PDF

Nathan, C. F., H. W. Murray, M. E. Wiebe, and B. Y. Rubin. Identification of interferon-g as the lymphokine that activates human macrophage oxidative metabolism and antimicrobial activity. J. Exp. Med. 158: 670-689, 1983 PDF

Nathan, C. F., G. Kaplan, W. R. Levis, A. Nusrat, M. D. Witmer, S. A. Sherwin, C. K. Job, C. R. Horowitz, R. M. Steinman, and Z. A. Cohn. Local and systemic effects of intradermal recombinant interferon-γ in patients with lepromatous leprosy. New Engl. J. Med. 315:6-15, 1986 PDF

Tsunawaki, S., M. Sporn, A. Ding, and C. Nathan. Deactivation of macrophages by transforming growth factor-ß. Nature 334:260-262, 1988 PDF

   Lepromatous leprosy showing bacilli in macrophages infiltrating the skin (left), and 6 days after injection of interferon-γ (right) (NEJM 1986).

   Lepromatous leprosy showing bacilli in macrophages infiltrating the skin (left), and 6 days after injection of interferon-γ (right) (NEJM 1986).

 

Analyses of neutrophil function and inflammation. Our lab discovered that integrin-mediated adherence synergizes with soluble agonists like tumor necrosis factor (TNF) to activate neutrophils to secrete oxidants at levels orders of magnitude higher than had been previously observed. Expanding from studies of macrophage and neutrophil ROS production and control, we developed innovative overviews of how inflammation is controlled and how control fails.

Nathan, C. Neutrophil activation on biological surfaces: Massive release of hydrogen peroxide in response to products of macrophages and lymphocytes. J. Clin. Invest. 80:1550-1560, 1987 PDF

Jin, F., C. Nathan, D. Radzioch and A. Ding. Secretory leukocyte protease inhibitor: a macrophage product induced by and antagonistic to bacterial lipopolysaccharide. Cell 88:417-426, 1997 PDF

Nathan, C. Inflammation: Points of control. Nature 420: 846-852, 2002 PDF

Nathan, C. and A. Ding. Non-resolving inflammation. Cell 140: 871-882, 2010 PDF

 

Biochemical and biological characterization of inducible nitric oxide synthase. Our lab pioneered the study of iNOS.

Stuehr, D. J., S. S. Gross, I. Sakuma, R. Levi, and C. F. Nathan. Activated murine macrophages secrete a metabolite of arginine with the bioactivity of endothelium-derived relaxing factor and the chemical reactivity of nitric oxide. J. Exp. Med. 169: 1011-1020, 1989 PDF

Xie, Q.-w., H. Cho, J. Calaycay, R. A. Mumford, K. M. Swiderek, T. D. Lee, A. Ding, T. Troso, and C. Nathan. Cloning and characterization of inducible nitric oxide synthase from mouse macrophages. Science 256:225-228, 1992 PDF

MacMicking, J. D., C. Nathan, G. Hom, N. Chartrain, M. Trumbauer, K. Stevens, Q.-w. Xie, K. Sokol, D. S. Fletcher, N. Hutchinson, H. Chen, and J. S. Mudgett. Altered responses to bacterial infection and endotoxic shock in mice lacking inducible nitric oxide synthase. Cell 81:641-650, 1995 PDF

MacMicking, J. D., R. J. North, R. LaCourse, J. S. Mudgett, S. K. Shah and C. F. Nathan. Identification of nitric oxide synthase as a protective locus against tuberculosis. Proc. Natl. Acad. Sci. USA. 94:5243-5248, 1997 PDF

                                                          iNOS-deficient mice succumb to rapid growth of Mtb (PNAS 1997).

                                                          iNOS-deficient mice succumb to rapid growth of Mtb (PNAS 1997).

 

Interaction of Mtb with the host and development of inhibitors. Studies of macrophage activation led to iNOS and that led to host-pathogen interactions in TB. Our lab identified many new enzymes or enzyme functions in Mtb and identified inhibitors of most of them, including the first compounds that selectively kill non-replicating bacteria and the first compounds that kill bacteria by inhibiting protein breakdown.

Bryk, R., P. Griffin and C. Nathan. Peroxynitrite reductase activity of bacterial peroxiredoxins. Nature 407, 211-215, 2000 PDF

Bryk, R., C. Lima, H. Erdjument-Bromage, P. Tempst and C. Nathan. Metabolic enzymes of mycobacteria linked to antioxidant defense by a thioredoxin-like protein. Science 295: 1073-1077, 2002 PDF

Darwin, K. H., S. Ehrt, J.-C. Gutierrez-Ramos, N. Weich and C. F. Nathan. The proteasome of Mycobacterium tuberculosis is required for resistance to nitric oxide. Science 302: 1963-1966, 2003 PDF

Lin, G., D. Li, L. P. Sorio de Carvalho, H. Deng, H. Tao, G. Vogt, K. Wu, J. Schneider, T. Chidawanyika, J. D. Warren, H. Li and C. Nathan. Inhibitors selective for mycobacterial versus human proteasomes. Nature 461: 621-626, 2009 PDF

                                                         Mtb proteasome core (PrcBA) (Lin et al., Mol Micro 59:  1417, 2006).

                                                         Mtb proteasome core (PrcBA) (Lin et al., Mol Micro 59:  1417, 2006).

 

Antibiotic development and public policy. Early stage drug discovery for tuberculosis led to appreciation of the global crisis in antimicrobial resistance. We called for “open labs” to address this, participated in setting up open labs and worked to bring the antimicrobial resistance crisis to the attention of a wider audience.

Nathan, C. Antibiotics at the crossroads. Nature 431: 899-902, 2004 PDF

Nathan, C. Aligning pharmaceutical innovation with medical need. Nature Medicine 13: 304-308, 2007 PDF

Nathan, C. Bacterial pathogenesis: Fresh approaches to anti-infective therapies. Science Translational Medicine 4: 1-13, 2012 PDF

Nathan, C. and O. Cars.  Antibiotic Resistance: Problems, Progress and Prospects. New Engl. J. Med. 371: 1761-3, 2014 PDF