 |
Michael Glickman, MD Assistant Member, Infectious Disease Service;
Head, Laboratory of Microbial Pathogenesis;
Assistant Member, Sloan-Kettering Institute;
Assistant Professor of Medicine and Immunology,
Weill Medical College of Cornell University |
|
|
Phone
212-639-3191
Education
MD, Columbia University College
of Physicians and Surgeons
Residencies
Internal Medicine, Massachusetts General Hospital
Fellowship
Infectious Diseases, Montefiore Medical Center - Albert Einstein College of Medicine
Board Certification
Internal Medicine; Infectious Diseases
Academic Appointments
Weill Medical College of Cornell University
Hospital Appointments
Memorial Hospital for Cancer and Allied Diseases
Research Interests
Our laboratory investigates the pathogenesis of infection with Mycobacterium tuberculosis (Mtb) through a multidisciplinary approach that includes bacterial genetics, lipid biochemistry, and immunology. Tuberculosis remains a major cause of mortality worldwide and new antimicrobials that would shorten TB chemotherapy are badly needed. The unique cell envelope of Mtb is the target of multiple currently available antimycobacterial agents and has been suspected to be important for virulence. We are investigating the role of the Mtb cell envelope in pathogenesis through the characterization of bacterial mutants deficient in the synthesis of defined cell envelope compounds. Through this approach, we have delineated the crucial role of mycolic acid cyclopropane residues in the interaction of Mtb with the murine host. Mycolic acids are very long chain branched fatty acids that are only synthesized by mycobacteria. Of all mycobacteria, only pathogenic species modify their mycolic acids with cyclopropane residues through the action of a family of mycolic acid methyltransferase genes. We have found that perturbation of the cyclopropane content of the Mtb cell envelope through genetic deletion of individual cyclopropane synthetase genes alters the symbiotic behavior of Mtb in mouse models of bacterial persistence. These cyclopropane synthetase mutants invoke distinct inflammatory histopathology, suggesting a role for individual cyclopropyl residues on mycolic acids in modulating the host immune response. These studies suggest that the exquisite chemical diversity of the Mtb cell envelope is an elaborate system of hydrophobic effector molecules that mediate host-pathogen interactions.
Our future work will focus on understanding the mechanisms by which the fine chemical structure of the Mtb cell envelope mediates host-pathogen interactions. These studies may identify novel targets for antimycobacterial drug development that would target persisting bacilli. In addition, understanding the host receptors that recognize these microbial products will lead to fundamental insights into the distinctive immunopathology of M. tuberculosis infection and into immune recognition of nonprotein microbial effector molecules.
Recent Publications
Landry, D.W., Zhao, K., Yang, G.X., Glickman, M.S., and T.M. Georgiadis. (1993) Antibody-catalyzed degradation of cocaine. Science. 259: 1899-1901.[PubMed Abstract]
Glickman, M.S. and R.S. Klein (1997) Acute epiglottis due to Pasteurella multocida in an adult without animal exposure. Emerging Infectious Diseases. 3: 408-409
Glickman, M.S., Cox J.S. and W.R. Jacobs Jr. (2000) A novel mycolic acid cyclopropane synthetase is required for cording, persistence, and virulence of Mycobacterium tuberculosis. Molecular Cell. 5: 717-727.[PubMed Abstract]
Glickman, M.S., Cahill, S.M. and W.R. Jacobs Jr. (2001) The mycobacterium tuberculosis cmaA2 gene encodes a mycolic acid trans cyclopropane synthetase. Journal of Biological Chemistry. 276: 2228-2233. [PubMed Abstract]
Glickman, M.S. and W.R. Jacobs Jr. (2001) Microbial Pathogenesis of Mycobacterium tuberculosis: dawn of a discipline. Cell. 104: 477-485. [PubMed Abstract]
Huang C.C., Smith C.V., Glickman M.S., Jacobs W.R. Jr., and J.C. Sacchettini. (2002) Crystal structures of mycolic acid cyclopropane synthases from Mycobacterium tuberculosis. Journal of Biological Chemistry. 277: 11559-69. [PubMed Abstract]
Glickman, M.S. (2003) The mmaA2 gene of Mycobacterium tuberculosis encodes the distal cyclopropane synthase of the alpha mycolic acid. Journal of Biological Chemistry. 278: 7844-7849. [PubMed Abstract]
Otero, J., Jacobs, W.R. Jr., and Glickmam, M.S. (2003) Efficient allelic exchange and transposon mutagenesis in Mycobacterium avium by specialized transduction. Appl Environ Microbiol. Sep;69(9):5039-44 [PubMed Abstract]
Rao,V., Fujiwara, N., Porcelli, S.A., and Glickman, M.S. (2005) M. tuberculosis controls host innate immune activation through cyclopropane modification of a glycolipid effector molecule. J Exp Med. Feb 21:201(4): 535-43. [PubMed Abstract]
Gong C. Bongiorno P, Martins A., Stephanou NC, Zhu H, Shuman S*, Glickman, M.S.* (2005) Mechanism of nonhomologous end-joining in mycobacteria: a low fidelity repare system driven by Ku, ligase D and ligase C. Nat Struct Mol Biol. Apr;12(4): 304-12. [PubMed Abstract] *Corresponding Authors
Makinoshima H, Glickman MS. (2005) Regulation of Mycobacterium tuberculosis cell envelope composition and virulence by intramembrane proteolysis. Nature. July 21: 436(7049):406-9. [PubMed Abstract]
Rao V, Gao F, Chen B, Jacobs WR, Glickman MS. (2006) Trans-cyclopropanation of mycolic acids on trehalose dimycolate suppresses Mycobacterium tuberculosis-induced inflammation and virulence. J Clin Invest. Jun 1;116(6):1660-1667. [PubMed Abstract]
Akey, D., Martins, A., Aniukwu, J., Glickman, M.S., Shuman, S., and Berger, J.M. 2006. Crystal structure and nonhomologous end-joining function of the ligase component of Mycobacterium DNA ligase D. J Biol Chem 281:13412 13423. [PubMed Abstract]
Zhu, H., Nandakumar, J., Aniukwu, J., Wang, L.K., Glickman, M.S., Lima, C.D., and Shuman,S. 2006. Atomic structure and nonhomologous end-joining function of the polymerase component of bacterial DNA ligase D. Proc Natl Acad Sci U S A 103:1711-1716.[PubMed Abstract]
Sinha, K.M., Stephanou, N.C., Gao, F., Glickman*, M.S., Shuman*, S. 2007. Mycobacterial UvrD1 is a Ku-dependent DNA helicase that plays a role in multiple DNA repair events, includingdouble-strand break repair. J Biol Chem 282: 15114-15125. *Corresponding Authors.
Stephanou, N.C., Gao, F., Bongiorno, P., Ehrt, S., Schnappinger, D., Shuman, S., Glickman, M.S. 2007. Mycobacterial Nonhomologous End Joining Mediates Mutagenic Repair of Chromosomal Double-Strand DNA Breaks. J Bact: [Epub ahead of print].[PubMed Abstract]
Related Commentary
L W Riley. (2006) Of mice, men, and elephants: Mycobacterium tuberculosis cell envelope lipids and pathogenesis. J Clin Invest. June 1, 2006; 116(6): 1475 - 1478. [PubMed Abstract]
