 |
Michael Glickman, MD Associate Member, Infectious Disease Service;
Head, Laboratory of Microbial Pathogenesis;
Associate Member, Sloan-Kettering Institute;
Associate 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
Stallings CL, Stephanou NC, Chu L, Hochschild A, Nickels BE, Glickman MS. CarD is an essential regulator of rRNA transcription required for Mycobacterium tuberculosis persistence. Cell. 2009 Jul 10;138(1):146-59. [PubMed Abstract]
Barkan D, Liu Z, Sacchettini JC, Glickman MS. Mycolic acid cyclopropanation is essential for viability, drug resistance, and cell wall integrity of Mycobacterium tuberculosis. Chem Biol. 2009 May 29;16(5):499-509. [PubMed Abstract]
Sinha KM, Glickman MS, Shuman S. Mutational Analysis of Mycobacterium UvrD1 Identifies Functional Groups Required for ATP Hydrolysis, DNA Unwinding, and Chemomechanical Coupling. Biochemistry. 2009 Apr 22. [PubMed Abstract]
El-Hajj HH, Marras SA, Tyagi S, Shashkina E, Kamboj M, Kiehn TE, Glickman MS, Kramer FR, Alland D. Use of sloppy molecular beacon probes for identification of mycobacterial species. J Clin Microbiol. 2009 Apr;47(4):1190-8. [PubMed Abstract]
Sinha KM, Stephanou NC, Unciuleac MC, Glickman MS*, and Shuman S*. Domain requirements for DNA unwinding by mycobacterial UvrD2, an essential DNA helicase. Biochemistry. 2008; 47:9355-64. *Co-Corresponding Authors. [PubMed Abstract]
Gallegos AM, Pamer EG*, and Glickman, MS*. Delayed protection by ESAT-6 specific effector CD4+ T cells following airborne M. tuberculosis infection. J Exp Med. 2008; 205:2359-68.*Co-Corresponding Authors. [PubMed Abstract]
Aniukwu J, Glickman MS*, Shuman S*. The pathways and outcomes of mycobacterial NHEJ depend on the structure of the broken DNA ends. Genes Dev. 2008; 22: 512-27. *Co-Corresponding Authors. [PubMed Abstract]
Velmurugan K, Chen B, Miller JL, Azogue S, Gurses S, Hsu T, Glickman MS, Jacobs Jr. WR, Porcelli SA, Briken V. Mycobacterium tuberculosis nuoG Is a virulence gene that inhibits apoptosis of infected host cells. Plos Pathog. 2007; 3: 972-980. [PubMed Abstract]
Shuman S, Glickman MS. Bacterial DNA repair by non-homologous end joining. Nat Rev Microbiol. 2007; 5(11):852-61. [PubMed Abstract]
Martiniuk F, Rao SD, Rea TH, Glickman MS, Giovinazzo J, Rom WN, Cabrera A, Levis WR. Leprosy as immune reconstitution inflammatory syndrome in HIV-positive persons. Emerg Infect Dis. 2007; 13:1438-1440. [PubMed Abstract]
Stephanou NC, Gao F, Bongiorno P, Ehrt S, Schnappinger D, Shuman S, Glickman MS. Mycobacterial Nonhomologous End Joining Mediates Mutagenic Repair of Chromosomal Double-Strand DNA Breaks. J Bacteriol. 2007; 189(14):5237-46. [PubMed Abstract]
Sinha KM, Stephanou NC, Gao F, Glickman* MS, Shuman* S. Mycobacterial UvrD1 is a Ku-dependent DNA helicase that plays a role in multiple DNA repair events, including double-strand break repair. J Biol Chem. 2007; 282: 15114-15125. *Corresponding Authors. [PubMed Abstract]
Rao V, Gao F, Chen B, Jacobs Jr. WR, and Glickman MS. Trans-cyclopropanation of mycolic acids on trehalose dimycolate suppresses Mycobacterium tuberculosis -induced inflammation and virulence. J Clin Invest. 2006; 116:1660-1667. [PubMed Abstract]
Zhu H, Nandakumar J, Aniukwu J, Wang LK, Glickman MS, Lima CD, and Shuman S. Atomic structure and nonhomologous end-joining function of the polymerase component of bacterial DNA ligase D. Proc Natl Acad Sci USA. 2006; 103:1711-1716. [PubMed Abstract]
Akey D, Martins A, Aniukwu J, Glickman, MS, Shuman S, and Berger JM. Crystal structure and nonhomologous end-joining function of the ligase component of Mycobacterium DNA ligase D. J Biol Chem. 2006; 281:13412-13423. [PubMed Abstract]
Makinoshima H, Glickman MS. Site-2 proteases in prokaryotes: regulated intramembrane proteolysis expands to microbial pathogenesis. Microbes Infect. 2006; 8(7):1882-8. [PubMed Abstract]
