Horwitz, Marcus

Marcus Horwitz, MD

Distinguished Professor of Medicine

About  Research  Publications

Bio

Dr. Horwitz is Distinguished 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 Oswald Avery (formerly 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; the development of vaccines against tuberculosis and Select Agent diseases (tularemia, anthrax, plague, melioidosis and glanders); and development of new drugs and ultra-short course drug regimens to treat TB.

Current Research Projects

Atomic Model and Mutational Analysis of the Francisella tularensis Type VI Secretion System (T6SS)
F. tularensis subsp. tularensis (F. tularensis), the causative agent of tularemia, is an intracellular pathogen and Tier I Select Agent of bioterrorism. The Horwitz laboratory has described the life cycle of F. tularensis in human macrophages including its ingestion by a novel mechanism – looping phagocytosis; its entry into a unique fibrillar-coated phagosome that resists fusion with lysosomes and exhibits limited acquisition of lysosomal markers; its subsequent escape from the phagosome via a unique Type VI Secretion System (T6SS); and its intracytoplasmic replication. T6SSs, multi-protein nano-machines that inject bacterial effector molecules into target prokaryotic and eukaryotic cells, are important virulence determinants found in one-quarter of Gram-negative bacteria including many that cause serious human diseases. The Horwitz laboratory, in collaboration with the Hong Zhou laboratory, first described the atomic structure of the T6SS contracted sheath and more recently that of the central spike complex and the baseplate protein IglD. Current projects center on determining the atomic structure of the F. tularensis precontraction sheath, the composition and structure of the T6SS membrane complex, the structure of secreted effector proteins, and further delineating the composition and protein interactions of the secreted tube and spike complex.

Characterization of a Novel Mycobacterial Heme Acquisition System 
Iron is an essential nutrient for all pathogens, and intracellular pathogens must acquire it under the iron-limiting conditions within the host. It has long been known that Mycobacterium tuberculosis (Mtb), the agent of TB, has a siderophore-mediated iron acquisition (SMIA) system. In previous studies, the Horwitz laboratory determined the structure of the extracellular siderophores of Mtb known as exochelins (or exomycobactins). Subsequently, the Horwitz laboratory made the unexpected discovery that Mtb additionally has a heme-iron acquisition (HIA) system, and in collaboration with the Celia Goulding laboratory at UCI, characterized several genes involved in this system. Recently, the Horwitz laboratory identified ppe37, an iron-regulated PPE family gene, and demonstrated that it is essential for HIA. The Horwitz laboratory also showed that a mutation in this gene explains the profound defect in HIA of the BCG vaccine. Current projects seek to further understand the role of key molecular participants in the HIA pathway.

Vaccines against Tuberculosis and Leprosy
TB kills ~1.8 million people per year globally and a better vaccine is needed. The Horwitz laboratory developed the first vaccine against tuberculosis more potent than BCG, the currently used vaccine. This live recombinant vaccine, called rBCG30, was the first replacement vaccine for BCG to enter human clinical trials. rBCG30 also induces superior protection than BCG against Mycobacterium bovis, the agent of bovine tuberculosis, and Mycobacterium leprae, the agent of leprosy. The Horwitz laboratory also developed the first replication-limited recombinant BCG vaccine [rBCG(mbtB)30], a vaccine that is both safer and more potent than BCG and designed specifically for HIV-positive infants and adults in whom conventional BCG can disseminate and cause serious disease. In addition, the Horwitz laboratory developed the first defined heterologous booster vaccine demonstrated to augment the level of protective immunity induced by BCG. Current laboratory projects seek to develop even more potent recombinant prime vaccines including live attenuated replication- and persistence-limited M. tuberculosis vaccines with enhanced antigen-presentation, and booster vaccines against tuberculosis including a live attenuated recombinant Listeria-vectored booster vaccine expressing nine immunoprotective M. tuberculosis antigens.

Single Vector Platform Vaccines against Tier 1 Select Agents and Emerging Pathogens 
The most practical way to protect against Tier 1 Select Agents of bioterrorism (especially, the bacterial agents of tularemia, anthrax, plague, melioidosis and glanders) is a safe and effective vaccine. Currently, no licensed vaccines exist against tularemia, plague, and melioidosis, and the licensed vaccine against anthrax is poorly effective and cumbersome to administer. Practically speaking, a single platform vaccine against multiple Tier 1 Select Agents of bioterrorism is highly desirable, as it would simplify manufacture, regulatory approval, and clinical evaluation; allow administration of multiple vaccines simultaneously and hence be more acceptable; and lower costs. The Horwitz laboratory has developed a novel safe and highly immunogenic plug-and-play Single Vector Platform for expressing key immunoprotective antigens of Tier 1 Select Agents based upon its novel vector LVS ΔcapB, derived from F. tularensis subsp. holarctica, and demonstrated exceptionally potent vaccines against all five of the aforementioned Tier 1 Select Agent diseases as well as an oral universal vaccine against Covid-19. Current projects seek to further develop these vaccines for FDA approval, to develop single multi-pathogen vaccines suitable for needle-free delivery by the oral or intranasal routes of administration, and to develop a pan-SARS-MERS vaccine. In addition, current studies seek to understand molecular and functional correlates of immune protection against tularemia and melioidosis.

Identification of Novel Synergistic Ultra-Short Universal Tuberculosis Drug Regimens
Current treatments for TB require exceedingly prolonged administration of multiple antibiotics, often resulting in poor adherence and consequently drug resistance. Identifying synergistic drug combinations among TB drugs has been stymied by the impossibility of studying billions of possible drug-dose combinations. To deal with this problem, the Horwitz laboratory has collaborated with the Chih-Ming Ho laboratory to employ an artificial intelligence-enabled Parabolic Response Surface (PRS) platform in concert with an in vitro M. tuberculosis-infected human macrophage cell culture assay amenable to high throughput screening; the approach dramatically reduced the number of tests required to identify highly effective TB drug regimens. Once such regimens were identified, the Horwitz laboratory used the PRS approach to optimize drug doses of select TB drug regimens in vivo. Using this approach, the Horwitz laboratory have identified novel regimens that are far superior to the Standard Regimen used to treat pulmonary TB, reducing the treatment time required to achieve relapse-free cure in mice by 80-85% compared with the Standard Regimen. Several PRS regimens comprising approved drugs are universal regimens suitable for treating both drug-sensitive and drug-resistant TB. One ultra-short course treatment regimen for active tuberculosis is currently being investigated in a clinical trial in Haiti and South Africa. In addition, the Horwitz laboratory is studying the efficacy in non-human primates of a novel ultra-short treatment regimen for latent tuberculosis (LTBI).

Targeted Controlled-Release Nanotherapeutics against Infectious Diseases
Nanoparticles for delivery of antibiotics are especially promising for the treatment of infectious diseases caused by intracellular pathogens, such as M. tuberculosis and F. tularensis, because macrophages, the primary host cells for these etiologic agents, are professional phagocytes that avidly ingest nanoparticles. By targeting nanoparticle drug-delivery systems to the site of infection and to the host cells at that site, and by releasing the drugs only intracellularly in host cells, nanotherapeutics have the potential to increase the therapeutic index of the drugs by orders of magnitude. The Horwitz laboratory, in collaboration with the laboratory of Jeffrey Zink at UCLA, has been developing and optimizing multifunctional stimulus-responsive mesoporous silica nanoparticles (MSNs) for delivery of antibiotics to treat tuberculosis and tularemia using in vitro and in vivo models. These MSNs contain internal pores that are loaded with antibiotic, after which the pores are capped by a stimulus responsive molecule. When administered to the host, these MSNs are rapidly and selectively ingested by host macrophages, and they subsequently release the drug contained within their pores in response to an intramacrophage signal - e.g. a lowering of the pH or a change in redox potential - that displaces or changes the configuration of the capping molecule such that the drug escapes from the pores and kills intracellular bacteria including M. tuberculosis and F. tularensis. These drug-loaded nanoparticles are substantially more effective than an equivalent amount of free drug in treating TB in a mouse model of pulmonary tuberculosis and in treating tularemia in a mouse model of pneumonic tularemia. Current studies are aimed at optimizing PRS drug regimens for inhalation delivery so as to further reduce the time needed to treat TB.

High Throughput Screening for Inhibitors of the F. tularensis Type VI Secretion System     
T6SSs are found in over one-quarter of Gram-negative bacteria and are critical to the virulence of many pathogens of major clinical significance. As such, it presents an attractive and novel target for drug development. The Horwitz laboratory has recently developed novel assays for identifying specific inhibitors of the Francisella T6SS that are amenable to high throughput screening, and in collaboration with Robert Damoiseaux, Director of the UCLA Molecular Screening Shared Resource (MSSR) facility, is screening libraries of small molecules to identify lead compounds that block T6SS assembly and secretion.

High Throughput Screening for Inhibitors of the M. tuberculosis Type VII Secretion System (T7SS)
Better drugs are needed to combat the global emergence of drug resistant strains of M. tuberculosis. Attractive and novel targets not previously exploited for drug development are the newly identified T7SSs that transport proteins essential to virulence through the M. tuberculosis hydrophobic cell wall. The Horwitz laboratory has developed a highly specific ELISA assay for T7SS function suitable for high-throughput screening of small molecules that block T7SS secretion.

Publications

  1. Clemens, D.L., P. Ge, B-Y Lee, M.A. Horwitz,*and Z. H. Zhou* (*Corresponding Authors). 2015. Atomic structure of T6SS reveals interlaced array essential to function. Cell 160:940-951. PMID: 25723168. PMCID: PMC4351867. NIHMSID: NIHMS665122 
    doi: 10.1016/j.cell.2015.02.005.
  2. Wu, Y-C., T-H. Wu, D. L. Clemens, B-Y. Lee, X. Wen, M.A Horwitz, M. A. Teitell, and P-Y. Chiou. 2015. Massively parallel delivery of large cargo into mammalian cells with light pulses. Nat Methods 12:439-444. Epub 2015-04-06. PMID: 25849636. PMCID: PMC5082232. NIHMSID: NIHMS823163 doi: 10.1038/nmeth.3357.
  3. Hwang, A., B-Y. Lee, D.L. Clemens, B.J. Dillon, J.I. Zink, and M.A. Horwitz. 2015. pH-responsive isoniazid-loaded nanoparticles markedly improve tuberculosis treatment in mice. Small 11(38):5065-5078. Epub 2015-07-20. PMID: 26193431. NIHMSID 723094. PMCID – PMC5628743. doi: 10.1002/smll.201500937.
  4. Li, Z., Clemens, D.L., Lee, B-Y, Dillon, B.J., Horwitz, M.A., Zink, J.I. 2015. Mesoporous Silica nanoparticles with pH – sensitive nanovalves for delivery of moxifloxacin provide improved treatment of lethal pneumonic tularemia. ACS Nano. 9(11):10778-10789. Epub 2015-10-09. PMID: 26435204. PMCID-in process. doi:10.1021/acsnano.5b04306
  5. Cunningham, C., A. Champhekar, M.V. Tullius, B.J. Dillon, A. Zhen, J. de la Fuente, J. Herskovitz, H. Elsaesser, E.B. Wilson, S.G. Kitchen, M.A. Horwitz, S.J. Bensinger, S. Smale and D.G. Brooks. 2016. Type I and type II interferon coordinately regulate suppressive dendritic cell fate and function during viral persistence. PLOS Pathogens. Jan. 25, 2016. 12(1):e1005356. PMID: 26808628. PMCID: PMC4726812. doi: 10.1371/journal.ppat.1005356.
  6. Silva A., B-Y. Lee, D.L. Clemens, T. Kee, X. Ding, C-M Ho, and M.A. Horwitz. 2016. Output-driven Feedback System Control platform optimizes combinatorial therapy of tuberculosis using a macrophage cell culture model. Proc. Natl. Acad. Sci. USA. E2172-2179. Epub 2016-03-28. PMID: 27035987. PMCID: PMC4839402.  doi: 10.1073/pnas.1600812113.
  7. Lee, B-Y., Z. Li, D.L. Clemens, B.J. Dillon, A.A. Hwang, J.I. Zink, and M.A. Horwitz. 2016. Redox-triggered release of moxifloxacin from mesoporous silica nanoparticles functionalized with disulfide snap-tops enhances efficacy against pneumonic tularemia in mice. Small 12 (27): 3690-3702. EPub 2016-06-01. PMID: 27412305. PMCID-in process. doi: 10.1002/smll.201600892
  8. Jia, Q., R. Bowen, R., B-Y. Lee, B.J. Dillon, S. Masleša-Galić, and M.A. Horwitz. 2016. Francisella tularensis Live Vaccine Strain deficient in capB and overexpressing the fusion protein of IglA, IglB, and IglC from the bfr promoter induces improved protection against F. tularensis respiratory challenge. Vaccine 34:4969-4978. PMID: 27577555. PMCID: PMC5028307. NIHMSID: NIHMS813638 doi: 10.1016/j.vaccine.2016.08.041.
  9. Lee, B-Y., D.L. Clemens, A. Silva, B.J. Dillon, S. Masleša-Galić, S. Nava, X. Ding, C-M Ho and M.A. Horwitz. 2017. Drug Regimens Identified and Optimized by Output-Driven Platform Markedly Reduce Tuberculosis Treatment Time. Nature Comm. 8:14183 PMID: 28117835. PMCID: PMC5287291. doi: 10.1038/ncomms14183.
  10. Ruehle, B., D.L. Clemens, B-Y. Lee, M.A. Horwitz, and J.I. Zink. 2017. Pathogen-specific cargo delivery platform based on mesoporous silica nanoparticles. J. Am. Chem. Soc. 139(19):6663-6668. Epub 2017 May 5. PMID: 28437093. doi: 10.1021/jacs.7b01278.
  11. Stefanova, D., A. Raychev, J. Arezes, P.P. Ruchala, V.R. Gabayan, M. Skurnik, B.J. Dillon, M.A. Horwitz, T. Ganz, Y. Bulut, and E. Nemeth. 2017. Endogenous hepcidin and its agonist mediate resistance to selected infections by clearing non-transferrin-bound iron. Blood. 130(3):245-257. Epub 2017 May 2. PMID: 28465342. PMCID: PMC5520472. doi: 10.1182/blood-2017-03-772715.
  12. Jia, Q., B.J. Dillon, S. Masleša-Galić, and M.A. Horwitz. 2017. Listeria-vectored vaccine expressing the Mycobacterium tuberculosis 30 kDa major secretory protein via the constitutively active prfA* regulon boosts BCG efficacy against tuberculosis. Infect. Immun. Epub 2017 June 19. PMID: 28630063. PMCID: PMC55633566. doi: 10.1128/IAI.00245-17.
  13. Jia, Q., R. Bowen, B.J. Dillon, S. Masleša-Galić, B.T. Chang, A.C. Kaidi, and M.A. Horwitz. 2018. Single vector platform vaccine protects against lethal respiratory challenge with Tier 1 select agents of anthrax, plague, and tularemia. Scientific Reports 8:7009. May 3, 2018. PMID: 29725025 PMCID: PMC5934503 doi: 10.1038/s41598-018-24581-y
  14. Clemens, D.L., B-Y. Lee, and M.A. Horwitz. 2018. The Francisella Type VI Secretion System. Frontiers in Cellular and Infection Microbiology 8:121, April 23, 2018. PMID: 29740542 PMCID: PMC5924787 doi:10.3389/fcimb.2018.00121.
  15. Jia, Q. and M.A. Horwitz. 2018. Live attenuated tularemia vaccines for protection against respiratory challenge with virulent F. tularensis subsp. tularensis. Frontiers in Cellular and Infection Microbiology 8:154. PMID: 29868510 PMCID: PMC5963219 doi:10.3389/fcimb.2018.00154.
  16. Chen, W., C-A Cheng, B-Y. Lee, D.L. Clemens, W-Y. Huang, M.A. Horwitz and J.I. Zink. 2018. A facile strategy enabling both high loading and high release amounts of water-insoluble drugs using mesoporous silica nanoparticles. ACS Applied Materials & Interfaces. Epub September 13, 2018. DOI: 10.1021/acsami.8b09069
  17. Lee , B-Y., D.L. Clemens , A. Silva, B.J. Dillon, S. Masleša-Galić, S. Nava, C-M. Ho, and M.A. Horwitz 2018. Ultra-rapid near universal TB drug regimen identified via parabolic response surface platform cures mice of both conventional and high susceptibility. PLoS One . 2018 Nov 14;13(11):e0207469. PMID: 30427938. doi: 10.1371/journal.pone. 0207469 . eCollection 2018.
  18. Clemens, D.L., B-Y Lee, S. Plamthottam, M.V. Tullius, R. Wang, C-J Yu, Z. Li, B.J. Dillon, J.I. Zink, and M.A. Horwitz. 2019. Nanoparticle formulation of moxifloxacin and intramuscular route of delivery improve antibiotic pharmacokinetics and treatment of pneumonic tularemia in a mouse model. ACS Infect. Dis. 5, 281–291. Epub 2018-11-27. DOI: 10.1021/acsinfecdis.8b00268
  19. Tullius, M.V., S. Nava, and M.A. Horwitz. 2019. PPE37 is essential for Mycobacterium tuberculosis heme-iron acquisition (HIA) and a defective PPE37 in Mycobacterium bovis BCG prevents HIA. Infect. Immun. 87(2) pii: e00540-18. E. Pub Nov. 19, 2018. PMID: 30455201 PMCID: PMC6346139 [Available on 2019-07-24]. doi:10.1128/IAI.00540-18.
  20. Clemens, D.L., B.-Y. Lee, A. Silva, B.J. Dillon, S. Masleša-Galić, S. Nava, X. Ding, C-M. Ho, and M.A. Horwitz. 2019. Artificial intelligence enabled parabolic response surface platform identifies ultra-rapid near-universal TB drug treatment regimens comprising approved drugs. PLoS One 14(5): e0215607. Published 10 May 2019. PMID: 31075149. PMCID: PMC6510528 DOI: 10.1371/journal.pone.0215607
  21. Chen, W., C.A. Glackin, M.A. Horwitz, and J.I. Zink. 2019. Nanomachines and other caps on mesoporous silica nanoparticles for drug delivery. Accounts of Chemical Research. DOI: 10.1021/acs.accounts.9b00116. Published online 13 May 2019. PMID: 31082188.
  22. Horwitz, M.A., D.L. Clemens, and B-Y. Lee. 2019. AI-Enabled Parabolic Response Surface Approach Identifies Ultra Short-Course Near-Universal TB Drug Regimens. Adv. Therap. e1900086. Published online 19 Sept. 2019. doi.org/10.1002/adtp.201900086
  23. Yang, X., D.L. Clemens, B-Y. Lee, Y. Cui, Z. H. Zhou, and M.A. Horwitz. 2019. Atomic Structure of Francisella T6SS Central Spike Reveals Unique a-Helical Lid and a Putative Cargo. Structure. 2019 Oct 29. pii: S0969-2126(19)30348-X. [Epub ahead of print]  doi: 10.1016/j.str.2019.10.007. PMID: 31677891 PMCID: PMC6939872
  24. Xu, W., L.M. Snell, M. Guo, G. Boukhaled, B.L. MacLeod, M. Li, M.V. Tullius, C.J. Guidos, M. Tsao, M. Divangahi, M.A. Horwitz, J. Liu and D.G. Brooks. 2021. Early innate and adaptive immune perturbations determine long-term severity of chronic virus and Mycobacterium tuberculosis coinfection. Epub 2021-01-29. Immunity 54:1-16 (March 9, 2021). PMID: 33515487. PMCID: PMC7946746. doi: 10.1016/j.immuni.2021.01.003.
  25. Jia, Q., H. Bielefeldt-Ohmann, R. M. Maison, S. Masleša-Galić, S.K. Cooper, R. A. Bowen and M.A. Horwitz. 2020/2021. Replicating bacterium-vectored vaccine expressing SARS-CoV-2 Membrane and Nucleocapsid proteins protects against severe COVID-19-like disease in hamsters. [bioRxiv, doi:10.1101/2020.11.17.387555 (2020)]. NPJ Vaccines (2021) 6:47. Epub 2021-03-30. PMID: 33236013. PMCID: PMC7685323. doi: 10.1038/s41541-021-00321-8.
  26. Jia, Q., S. Masleša-Galić, S. Nava and M.A. Horwitz. 2022. Listeria-vectored multi-antigenic tuberculosis vaccine enhances protective immunity against aerosol challenge with virulent Mycobacterium tuberculosis in BCG-immunized C57BL/6 and BALB/c mice. mBio. 13(3): e00687-22, EPub 1 June, 2022. PMID: 35642945. PMCID: PMC9239278. doi: 10.1128/mbio.00687-22.
  27. Liu, X., D.L. Clemens, B-Y. Lee, X. Yang, Z.H. Zhou, and M.A. Horwitz. 2022. Atomic structure of IglD demonstrates its role as a component of the baseplate complex of the Francisella type VI secretion system. mBio. 13(5) e01277-22. EPub: 2022-08-29.
    PMID: 36036641. PMCID: PMC9600919. doi: 10.1128/mbio.01277-22.
  28. Jia, Q., S. Masleša-Galić, S. Nava and M.A. Horwitz. 2022. Listeria-vectored multi-antigenic tuberculosis vaccine protects C57BL/6 and BALB/c mice and guinea pigs against Mycobacterium tuberculosis challenge. Communications Biology (2022) 5:138.  PMID: 36539517. PMCID: PMC9764316. doi: 10.1038/s42003-022-04345-1.
  29. Jia, Q., H. Bielefeldt-Ohmann, R. M. Maison, A. Hartwig, S. Masleša-Galić, R. A. Bowen and M.A. Horwitz. 2022. Oral administration of universal bacterium-vectored COVID-19 vaccine protects against severe COVID-19-like disease in Syrian hamsters. PMID: 36916971. PMCID: PMC10100875. doi: 10.1128/spectrum.05035-22.
  30. Zheng,X., X. Gui, L. Yao, J. Ma, Y. He, H. Lou, J. Gu, R. Ying, L. Chen, Q. Sun, Y. Liu, C-M. Ho, B-Y. Lee, D.L. Clemens, M.A. Horwitz, X. Ding, X. Hao, H. Yang, and W. Sha. 2023. Efficacy and safety of an innovative short-course regimen containing clofazimine for treatment of drug-susceptible tuberculosis: a clinical trial. Emerging Microbes & Infections (TEMI) EPub: March 6, 2023. PMID: 36872899. PMCID: PMC10026740. doi: 10.1080/22221751.2023.2187247.
  31. Mlynek, K.D., C.R. Cline, S.S. Biryukov, R.G. Toothman, B.A. Bachert, C.P. Klimko, J.L. Shoe, M. Hunter, Z.M. Hedrick, J.L. Dankmeyer, S. Mou, D.P. Fetterer, J. Qiu, E.D. Lee, C.K. Cote, Q. Jia, M.A. Horwitz & J.A. Bozue. 2023. The rLVS ΔcapB/iglABC vaccine provides potent protection in Fischer rats against inhalational tularemia caused by various virulent Francisella tularensis strains.Human Vaccines & Immunotherapeutics 19(3):2277083. Epub 2023-11-17. PMID: 37975637. PMCID: 10826624
  32. Tullius, M.V., R. A. Bowen, P.S. Back, S. Masleša-Galić, S. Nava, and M.A. Horwitz. 2024. LVS ΔcapB-vectored multiantigenic melioidosis vaccines protect against lethal respiratory Burkholderia pseudomallei challenge in highly sensitive BALB/c mice. mBio. 15(4): e00186-24. April 2024. PMID: 38511933 PMCID: 11005352