Marcus Horwitz, M.D.

Professor of Medicine

Dr. Horwitz is Professor of Medicine and Microbiology, Immunology, & Molecular Genetics.  He received his M.D. degree from Columbia U. College of Physicians and Surgeons and subsequently trained in Internal Medicine and Infectious Diseases at the Albert Einstein College of Medicine.  He served for two years as an Epidemic Intelligence Officer at the CDC and then trained in cellular physiology and immunology at The Rockefeller University.  From 1980-85, he was on the faculty of The Rockefeller University as an Assistant Professor and Associate Physician.  In 1985, he joined the faculty of UCLA as Professor of Medicine and of Microbiology, Immunology & Molecular Genetics and as Chief of the Division of Infectious Diseases, a position he held until 1992.  Dr. Horwitz is a fellow in the Infectious Diseases Society of America and a member of the American Society for Clinical Investigation.  His awards include the Squibb Award from the Infectious Diseases Society of America and election to Fellowship in the American Association for the Advancement of Science. His research has focused on intracellular parasitism, especially the immunobiology of the etiologic agents of Legionnaires' disease, leprosy, tuberculosis, and tularemia.  Current projects include the following:

 Vaccine Against Tuberculosis

              TB kills over 2 million people per year globally and a better vaccine is needed.  Dr. Horwitz's laboratory developed a vaccine more potent than BCG, the currently used vaccine.  This vaccine, called rBCG30, is now in human clinical trials.  Current laboratory projects seek to develop vaccines more potent than rBCG30 and to develop vaccines specifically for AIDS patients. 

 Vaccine Against Tularemia

               Francisella tularensis, the agent of tularemia, is a potential agent of bioterrorism, and no vaccine is currently available.  The Horwitz laboratory has identified several promising vaccine candidates and cloned and expressed the genes encoding them.  Current projects seek to develop and test novel recombinant vaccines against F. tularensis.

 Characterization of the Mycobacterium tuberculosis phagosome

               Dr. Horwitz's laboratory has demonstrated that M. tuberculosis enters a phagosome in human mononuclear phagocytes that interacts with the host cell endolysosomal pathway but arrests the normal maturation of that pathway.  Current studies employing cryosection immunogold electron microscopy and proteomics approaches are aimed at understanding the molecular basis for the arrested maturation of the M. tuberculosis phagosome.

 Characterization of the Francisella tularensis phagosome

               Dr. Horwitz's laboratory has demonstrated that F. tularensis enters a unique phagosome in human mononuclear phagocytes that is coated with a fibrillar structure.  The pathogen then arrests the maturation of the phagosome, inhibits its acidification, and finally lyses the phagosome to escape and multiply free in the cytoplasm.  Current projects seek to identify the molecular composition of the fibrillar coat on the phagosome and to understand the mechanism by which the organism escapes the phagosome.

 Development of Novel Antibiotics Against Mycobacterium tuberculosis

M. tuberculosis is rapidly developing resistance to all of the major antibiotics currently used to treat it.  The Horwitz laboratory is pursuing three independent approaches to the development of new antibiotics.

A.           Antisense Technology.  The Horwitz laboratory has previously demonstrated the feasibility of this approach to the development of antibiotics against M. tuberculosis.  Current studies seek to improve the uptake and potency of antisense compounds against M. tuberculosis. 

B.           Glutamine Synthetase Inhibitors.  The Horwitz laboratory has previously demonstrated that M. tuberculosis glutamine synthetase is an essential enzyme for bacterial virulence and that potent inhibitors of glutamine synthetase such as L-methionione-S-sulfoximine block bacterial growth in broth culture, in human macrophages and in vivo in guinea pigs.  Current studies are aimed a developing novel analogs of L-methionione-S-sulfoximine safe for use in humans.

C.           Mycolyl Transferase Inhibitors.  The Horwitz laboratory has previously identified the M. tuberculosis mycolyl transferase enzyme complex as a prime target for new antibiotics, and in collaborative studies, determined the three dimensional structure of the major mycolyl transferase enzyme.   Current projects are aimed at developing and testing novel mycolyl transferase inhibitors based on the structure of the active site of the enzyme.

Selected Recent Publications

 Horwitz, M.A., G. Harth, B.J. Dillon, and S. Malesa-Galic.  2000.  Recombinant BCG Vaccines Expressing the Mycobacterium tuberculosis 30 kDa Major Secretory Protein Induce Greater Protective Immunity Against Tuberculosis than Conventional BCG Vaccines in a Highly Susceptible Animal Model.  Proc. Natl. Acad. Sci. (USA). 97:13853-13858.

 Clemens, D.L., B-Y Lee, and M.A. Horwitz.  2000.  Deviant expression of Rab5 on phagosomes containing the intracellular pathogens Mycobacterium tuberculosis and Legionella pneumophila is associated with altered phagosomal fate. Infect. Immun.68:2671-2684.

 Clemens, D.L., B-Y. Lee, and M.A. Horwitz. 2002. The Mycobacterium tuberculosis phagosome in human macrophages is isolated from the host cell cytoplasm.  Infect. Immun. 70: 5800-5807.

 Clemens, D.L., B-Y. Lee, and M.A. Horwitz. 2004. Virulent and avirulent strains of Francisella tularensis prevent acidification & maturation of their phagosomes & escape into the cytoplasm in human macrophages. Infect. Immun.72:3204-17.

 Harth, G., P.C. Zamecnik, J-Y.Tang, D.Tabatadze, and M.A. Horwitz.  2000.Treatment of Mycobacterium tuberculosis with antisense oligonucleotides to glutamine synthetase mRNA inhibits glutamine synthetase activity, formation of the poly-L-glutamine/glutamate cell wall structure, and bacterial replication. Proc. Natl. Acad. Sci. (USA). 97:418-423.

 Harth, G., M.A. Horwitz, D.Tabatadze and P.C. Zamecnik. 2002.Targeting the Mycobacterium tuberculosis 30/32kDa mycolyl transferase complex as a therapeutic strategy against tuberculosis:  Proof of principle using antisense technology. Proc. Natl. Acad. Sci. USA 99:15614-15619.

 Tullius, M.V., G. Harth, and M.A. Horwitz. 2003. Glutamine synthetase GlnA1 is essential for growth of Mycobacterium tuberculosis in human THP-1 macrophages and guinea pigs.  Infect. Immun. 71:3927-3936.

 Harth, G. and M.A. Horwitz. 2003. Inhibition of Mycobacterium tuberculosis glutamine synthetase as a novel antibiotic strategy against tuberculosis: Demonstration of efficacy in vivo.  Infect. Immun. 71:456-464.

Anderson, D.H., G. Harth, M. A. Horwitz, and D. Eisenberg. 2001. An interfacial mechanism and a class of inhibitors inferred from two crystal structures of the Mycobacterium tuberculosis 30 kDa major secretory protein (Antigen 85B), a mycolyl transferase. J. Molec. Biol. 307:671-681.