Michael J. Holtzman, M.D.

Selma and Herman Seldin Professor
Internal Medicine
Pulmonary & Critical Care Medicine
Professor
Cell Biology and Physiology

Immunology Program
Molecular Microbiology and Microbial Pathogenesis Program
Molecular Cell Biology Program

  • 314-362-8970

  • 314-362-8973

  • 314-362-9009

  • 8052

  • 9950 Clinical Sciences Research Building

  • HOLTZMANM@WUSTL.EDU

  • https://pulmonary.wustl.edu/faculty/michael-j-holtzman-md/

  • http://www.mjholtzmanlab.com

  • innate immunity, macrophages, innate lymphocytes, dendritic cells, epithelial cells, interferon signal transduction, paramyxoviruses, picornaviruses, asthma, drug discovery

  • Pathogenesis and new therapeutics for viral infection and post-viral disease

Research Abstract:

My lab studies the role of viruses in causing acute infection and chronic disease, focusing on antiviral immune responses as pathways for pathogenesis and targets for drug discovery in respiratory diseases. We apply a multidisciplinary and translational approach to study cellular and animal models as well as human subjects. We showed that viral immunity depends on a special network of innate immune-response genes in host cells of the airway epithelial barrier, and we have focused on this network as a drug target for antiviral therapy. In particular, we have engineered the interferon-signaling pathway to identify new components of this pathway that safely and effectively improve control of viral infection. We have extended this strategy to discovery of small molecule interferon signal enhancer (SMISE) compounds that have just reached the stage of human clinical trials as antiviral drugs. We have also found that viruses can trigger long-term activation of an innate immune axis that includes a distinct epithelial stem cell niche and downstream immune cells in experimental models and in human subjects with chronic respiratory diseases such as asthma and COPD. This immune pathway leads to excess airway mucus production that is responsible for the morbidity and mortality from chronic respiratory disease, now the country’s third leading cause of death. To address this issue, we have also targeted this pathway using structure-based drug design to identify proprietary small molecules that interrupt kinase-dependent mucus production, thereby providing tool compounds for proof-of-concept and lead candidates for clinical application. Current efforts include defining and controlling immune cell activation and epithelial stem cell expansion and differentiation after viral infection.

Selected Publications:

Zhang, Y., Mao, D., Roswit, W. T., Jin, X., Patel, A. C., Patel, D. A., Agapov, E., Wang, Z., Tidwell, R. M., Atkinson, J. J., Huang, G., McCarthy, R., Yu, J., Yun, N. E., Paessler, S. L., Lawson, T. G., Omattage, N. S., Brett, T. J., and Holtzman, M. J. PARP9-DTX3L ubiquitin ligase targets host histone H2BJ and viral 3C protease to enhance interferon signaling and control viral infection. (2015) Nat. Immunol. 16:1215-1227 (selected for journal cover).

Wu, K., Byers, D. E., Jin, X., Agapov, E., Alexander-Brett, J., Patel, A. C., Cella, M., Gilfilan, S., Colonna, M., Kober, D. L., Brett, T. J., and Holtzman, M. J. TREM-2 promotes macrophage survival and lung disease after respiratory viral infection. (2015) J. Exp. Med. 212:681-697.

Holtzman, M. J., Byers, D. E., Alexander-Brett, J., and Wang, X. The role of airway epithelial cells and innate immune cells in chronic respiratory disease. (2014) Nat. Rev. Immunol. 14:686-698.

Patel, D. A., Patel, A. C., Nolan, W. C., Huang, G., Romero, A. G., Charlton, N., Agapov, E., Zhang, Y., and Holtzman, M. J. High-throughput screening normalized to biological response: application to antiviral drug discovery. (2014) J. Biomol. Screen. 19:119-130.

Byers, D. E., Alexander-Brett, J., Patel, A. C., Agapov, E., Dang-Vu, G., Jin, X., Wu, K., You, Y., Alevy, Y., Girard, J.-P., Stappenbeck, T. S., Patterson, G. A., Pierce, R. A., Brody, S. L., and Holtzman, M. J. (2013) Long-term IL-33-producing epithelial progenitor cells in chronic obstructive lung disease. J. Clin. Invest. 123:3967-3982. (selected for journal cover)

Alevy, Y. G., Patel, A. C., Romero, A. G., Patel, D. A., Tucker, J., Roswit, W. T, Miller, C. A., Heier, R., Byers, D. E., Brett, T. J., and Holtzman, M. J. (2012) IL-13-induced airway mucus production is attenuated by MAPK13 inhibition. J. Clin. Invest. 122:4555-4568.

Kim, E.Y., Battaile, J.T., Patel, A.C., You, Y., Agapov, E., Grayson, M.H., Benoit, L.A., Byers, D.E., Alevy, Y., Tucker, J., Swanson, S., Tidwell, R., Tyner, J.W., Morton, J.D., Castro, M., Polineni, D., Patterson, G.A., Schwendener, R.A., Allard, J.D., Peltz, G., and Holtzman, M.J. Persistent activation of an innate immune response translates respiratory viral infection into chronic lung disease. Nat Med 2008 14: 633-640.

Grayson, M. H., Cheung, D., Rohlfing, M. M., Kitchens, R., Spiegel, D. E., Tucker, J., Battaile, J., Alevy, Y., Yan, L., Agapov, E., Kim, E. Y., and Holtzman, M. J. Induction of high-affinity IgE receptor on lung dendritic cells during viral infection leads to mucous cell metaplasia. J Exp Med 2007 204: 2759-2769.

Tyner, J. W., Kim, E. Y., Ide, K., Pelletier, M. R., Roswit, W. T., Morton, J. D., Battaile, J. T., Patel, A. C., Patterson, G. A., Castro, M., Spoor, M. S., You, Y., Brody, S. L., and Holtzman, M. J. Blocking airway mucous cell metaplasia by inhibiting EGFR antiapoptosis and IL-13 transdifferentiation signals. J Clin Invest 2006 116: 309-321.

Tyner, J. W., Uchida, O., Kajiwara, N., Kim, E. Y., Patel, A.C., O’Sullivan, M.P., Walter, M. J., Schwendener, R. A, Cook, D. N., Danoff, T. M., and Holtzman, M. J. CCL5-CCR5 interaction provides antiapoptotic signals for macrophage survival during viral infection. Nat Med 2005 11: 1180-1187.

Last Updated: 8/24/2016 3:21:39 PM

The Holtzman Lab discovered a safe mechanism to enhance interferon signaling and improve immunity, based on dual activities of a PARP9-DTX3L ubiquitin ligase. The confocal image shows DTX3L co-localized with encephalomyocarditis virus (EMCV) 3C protease in the nucleus and cytosol of U3A cells overexpressing DTX3L, in this case in an inactive form to permit protease imaging at 5 hours after EMCV infection. DTX3L is stained green, and EMCV is stained red.
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