Profile-David Markovitz, M.D.

NAME: David M. Markovitz

eRA COMMONS USER NAME (credential, e.g., agency login): dmarkov

POSITION TITLE: Professor

EDUCATION/TRAINING

A. Personal Statement. My research, training experience, and ability to collaborate position me very well to develop new and innovative approaches to understanding basic biology and developing therapeutics. I head a laboratory group that includes four other faculty members and uses diverse experimental modalities to investigate issues in basic molecular immunology, virology and cell biology, all originating from the study of the interaction between viruses and human cells. Recent projects in our research group have also used such diverse modalities as NMR, crystallography, molecular dynamics modeling, glycoclusters, next-generation sequencing, bioinformatics, and animal models to work out mechanisms of pathogenesis and to design new agents to attack autoimmunity, viral disease, and cancer. Interdisciplinary work in my group has resulted in 92 publications, and I have supervised doctoral students, post-doctoral fellows, medical students, masters students, and undergraduates. I have a history of putting teams of investigators together to pursue projects in areas that have been previously unexplored. Our work on BanLec led to the first demonstration that the functions of a lectin (in this case mitogenicity and antiviral activity) can be separated through targeted engineering, and we went on to explain the atomic level basis for this divergence. Another large collaboration that I spearheaded involved geneticists, virologists, and bioinformatics experts studying the importance of human endogenous retroviruses. With multiple co-investigators, I have also worked to explore the basic biology of the biochemically distinct DEK protein, its role in diverse cellular processes, and its involvement in the pathogenesis and management of juvenile arthritis.

a. Contreras-Galindo, R., Kaplan, M.H., He, S., Contreras-Galindo, A.C., Gonzalez-Hernandez, M.J., Kappes, F., Dube, D., Chan, S.M., Robinson, D., Meng, F., Dai, M., Gitlin, S.D., Chinnaiyan, A.M., Omenn, G.S. and Markovitz, D.M. HIV infection reveals wide-spread expansion of novel centromeric human endogenous retroviruses. Genome Res., 2013; 23(9):1505-13. PMCID: PMC3759726.

b. Swanson, M.D., Boudreaux, D.M., Salmon, S., Chugh, J., Winter, H.C., Meagher, J.L., Andre, S., Murphy, P.V., Oscarson, S., Roy, R., King, S., Kaplan, M.H., Goldstein, I.J., Tarbet, E.B., Hurst, B.L., Smee, D.F., de la Fuente, C., Hoffman, H-H., Xue, Y., Rice, C.M., Schols, D., Garcia, J.V., Stuckey,J.A., Gabius, H-J., Al-Hashimi, H.M., and Markovitz, D.M. Engineering a therapeutic lectin: uncoupling mitogenicity from antiviral activity. Cell 2015; 163:746–758. PMID: 26496612

c. Mor-Vaknin, N., Saha, A., Legendre, M., Carmona-Rivera, C., Amin, M.A., Rabquer, B.J., Gonzales-Hernandez, M.J., Jorns, J., Mohan, S., Yalavarthi, S., Pai, D.A., Angevine, K., lmburg, S.J., Knight, J.S., Adams, B.S., Koch, A.E., Fox, D.A., Engelke, D.R., Kaplan, M.J., and Markovitz, D.M. DEK-targeting DNA aptamers as therapeutics for inflammatory arthritis. Nature Communications, 2017 Feb 6;8:14252. doi: 10.1038/ncomms14252. PMID: 28165452 PMCID: PMC5303823.

d. Mor-Vaknin, N., Punturieri, A., Sitwala, K., and Markovitz, D.M. Vimentin is secreted by activated macrophages. Nat. Cell Biol. 2003; 5:59-63.

B. Positions and Honors

Positions and Employment

1988-1994 Assistant Professor Division of Infectious Diseases, Department of Internal Medicine University of Michigan Medical Center, Ann Arbor, Michigan

1994-2002 Associate Professor (with tenure), Division of Infectious Diseases, Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, Michigan

2002-present Professor (with tenure), Division of Infectious Diseases, Department of Internal Medicine University of Michigan Medical Center, Ann Arbor, Michigan

Other Experience and Professional Memberships

Central Society for Clinical Research; American Society for Clinical Investigation; Association of American Physicians; Editorial Board – Journal of Virology, 2002-2007; FDA Vaccines and Related Biological Products Advisory Committee, 2002-2006; Research Committee, Infectious Diseases Society of America, 2009-2014 (Chair of the Committee 2011-2014); Board of Directors, American Physician Scientist Association, 2012-present

Honors

University of Minnesota, B.A., Magna Cum Laude 1976; National Cancer Institute – Clinical Investigator Award, 1990; Life and Health Insurance Medical Research Fund Scholar, 1991; American Society for Clinical Investigation, 1997; Burroughs Wellcome Clinical Scientist Award in Translational Research, 2003; Association of American Physicians, 2004; Transformative R01, Office of the Director, NIH, 2009; American Clinical and Climatological Association, 2012.

C. Contributions to Science

1. Throughout my career as a trainee and then as an independent investigator, much of my work has either directly focused on, or interconnected with, the pathogenic retroviruses that cause AIDS, HIV-1 and HIV-2. As I emerged as an independent investigator, I focused on the differences in the regulation of HIV-2 transcription as compared to HIV-1, as both viruses cause AIDS but HIV-2 much more slowly. These studies identified distinct differences in the enhancer elements of HIV-2 that mediate its response to T-cell activation, suggesting important ways that the two viruses could exhibit differential courses of disease causation. This work was also aimed at identifying the key cellular factors that mediate transcriptional activation following immune stimulation and therefore are likely to be involved in the immune response. Through these studies, we were able to clone an important, previously-identified cellular factor, DEK, showing that it interacted with a key enhancer element that mediates HIV-2 transcriptional activation. It was through this line of investigation that our efforts to understand the biology of the DEK protein, detailed below, were launched.

a. Gartner, S., Markovits, P., Markovitz, D.M., Kaplan, M.H., Gallo, R.C., and Popovic, M. The role of mononuclear phagocytes in HTLV-III/LAV infection. Science 1986; 233:215-219.

b. Markovitz, D.M., Hannibal, M., Perez, V.L., Gauntt, C., Folks, T.M., and Nabel, G.J. Differential regulation of human immunodeficiency viruses (HIVs): a specific regulatory element in HIV 2 responds to stimulation of the T-cell antigen receptor. Proc. Natl. Acad. Sci. USA 1990; 87:9098-9102.

c. Fu, G.K., Grosveld, G., and Markovitz, D.M. DEK, an autoantigen involved in a chromosomal translocation in acute myelogenous leukemia, binds to the human immunodeficiency virus type 2 enhancer. Proc. Natl. Acad. Sci., USA 1997; 94:1811-1815.

d. Faulkner, N.E., Hilfinger, J.M., and Markovitz, D.M. Protein phosphatase 2A activates the HIV-2 promoter through enhancer elements that include the pets site. J. Biol. Chem. 2001; 276(28):25804-25812.

2. The DEK protein is a biochemically distinct factor that has been implicated in the pathogenesis of cancer and, in its pro-inflammatory role, in the pathogenesis of juvenile arthritis. We have detailed the complex life cycle of DEK, wherein it serves as a crucial chromatin factor, is secreted and acts as a chemotactic factor, and can then be taken back up by other cells in a bioactive manner wherein it corrects the chromatin and DNA repair defects seen in cells that do not contain DEK. We have proven at the genetic level that DEK is vital to inflammation and is key to Neutrophil Extracellular Traps (NETs), and have developed an anti-DEK aptamer that has pronounced anti-inflammatory activity in a mouse model.

a. Kappes, F., Waldmann, T., Mathew, V., Yu, J., Zhang, L., Khodadoust, M.S., Chinnaiyan, A.M., Luger, K., Erhardt, S., Schneider, R., and Markovitz, D.M. The DEK oncoprotein is a su(var) that is essential to heterochromatin integrity. Genes Dev. 2011; 25:673-678. PMCID: PMC3070930.

b. Saha, A.K., Kappes, F., Mundade, A., Deutzmann, A., Rosmarin, D., Legendre, M., Chatain, N., Al-Obaidi, Z., Adams, B.S., Ploegh, H., Ferrando-May, E., Mor-Vaknin, N., and Markovitz, D.M. Intercellular trafficking of the nuclear oncoprotein DEK. Proc. Natl. Acad. Sci., USA. 2013; 110(17):6847-52. PMCID: PMC3637753.

d. Mor-Vaknin, N., Rivas, M., Legendre, M., Mohan, S., Yuanfan, Y., Mau, T., Johnson, A., Huang, B., Zhao, L., Kimura, Y., Spalding, S., Morris, P., Gottlieb, B.S., Onel, K., Olson, J.C., Edelheit, B., Shishov, M., Jung, L., Cassidy, E., Prahalad, S., Passo, M., Beukelman, T., Mehta, J., Giannini, E.H., Adams, B.S., Lovell, D.J., and Markovitz, D.M. High Levels of DEK Autoantibodies in Sera of Polyarticular JIA Patients and in Early Flare Following Cessation of Anti-TNF Therapy. Arthritis & Rheumatology 2018. (In Press).

3. Vimentin is a very highly-expressed cellular protein that has been termed the “conundrum of the intermediate filament family” because of its great abundance but unknown function. Indeed, Vimentin knock-out mice were, very surprisingly, not found to have a phenotype at first. In the process of studying the secretion of DEK, we made the paradigm-shifting observation that the vimentin intermediate filament protein is actually a secreted inflammatory factor. Using a mouse model, we went on to demonstrate that this protein plays a vital role in a key clinical setting involving unwanted inflammation: inflammatory bowel disease.

a. Mor-Vaknin, N., Punturieri, A., Sitwala, K., and Markovitz, D.M. Vimentin is secreted by activated macrophages. Nat. Cell Biol. 2003; 5:59-63.

b. Mor-Vaknin, N., Legendre, M., Yue, Y., Serezani, C.H.C., Garg, S.K., Jatzek, A., Swanson, M.D., Gonzalez-Hernandez, M.J., Teitz-Tennenbaum, S., Punturieri, A., Engleberg, N.C., Banerjee, R., Peters-Golden, M., Kao, J.Y., and Markovitz, D.M. Murine colitis is mediated by vimentin. Sci. Rep. 2013; 3:1045. PMCID: PMC3540396.

c. Russo, B. C., Stamm, L. M., Raaben, M., Kim, C. M., Kahoud, E., Robinson, L.R., Bose, S., Queiroz, A. L., Herrera, B. B., Baxt, L.A., Mor-Vaknin, N., Fu, Y., Molina, G., Markovitz, D. M., Whelan, S. P., and Goldberg, M. B. Intermediate filaments enable pathogen docking to trigger type 3 effector translocation. Nat Microbiol. 2016 Mar 7;1:16025. PMID: 27572444.

4. Eight percent of the human genome is, surprisingly, made up of ancient retroviruses that have insinuated themselves into our genetic inheritance. These retroviruses, termed human endogenous retroviruses (HERVs), have traditionally been thought to be genetic fossils that are incapable of replication. While it is not yet clear that these viruses can still undergo active, spreading, replication, we have shown that they can package and transmit viral RNA from one cell to another. Further, we have found that, surprisingly, contrary to other known retroviruses, these viruses assume both an RNA and DNA form, and both are infectious. Further, in studying the blood of living patients with HIV infection, we uncovered two completely new members of the HERV-K family, at least one of whose transcription is activated by the Tat protein of HIV. These particular HERVs were found to be in centromeres and to have spread from one centromere to the next. As centromeres are highly repetitive elements, they are very poorly defined in the human genome assembly, and therefore have been a last frontier in human genomics and genetics. Our findings have given us new “bar-codes” to study specific centromeres as well as allowing us to make the ground-breaking discovery that genetic exchange, probably due to homologous recombination, takes place between different centromeres.

a. Contreras-Galindo, R., Kaplan, M.H., He, S., Contreras-Galindo, A.C., Gonzalez- Hernandez, M.J., Kappes, F., Dube, D., Chan, S.M., Robinson, D., Meng, F., Dai, M., Gitlin, S.D., Chinnaiyan, A.M., Omenn, G.S. and Markovitz, D.M. HIV infection reveals wide-spread expansion of novel centromeric human endogenous retroviruses. Genome Res., 2013; 23(9):1505-13. PMCID: PMC3759726.

b. Dube, D., Contreras-Galindo, R., He, S., King, S.R., Gonzalez-Hernandez, M.J., Gitlin, S.D., Kaplan, M.H., and Markovitz, D.M. Genomic flexibility of Human Endogenous Retrovirus type K. J. Virol., 2014. Sep;88(17):9673-82. PMID: 24920813.

c. Zahn J., Kaplan M.H., Fischer S., Dai M., Meng F., Saja A.K., Cervantes P., Chan S., Dube D., Omenn G.S., Markovitz D.M., and Contreras-Galindo R. Expansion of a novel endogenous retrovirus throughout the pericentromeres of modern humans. Genome Biology. 2015 Apr 12;16(1):74. PMID: 25886262.

d. Contreras-Galindo, R., Fischer, S., Saha, A.K., Lundy, J.D., Cervantes, P.W., Mourad, M., Wang, C., Qian, B., Dai, M., Meng, F., Chinnaiyan, A., Omenn, G.S., Kaplan, M.H., and Markovitz. D.M. Rapid Molecular Assays to Study Human Centromere Genomics. Genome Res. 2017 Dec;27(12):2040-2049. doi: 10.1101/gr.219709.116. Epub 2017 Nov 15. PMID: 29141960.

5. Lectins have the potential to be used as antiviral agents due to their ability to bind sugars, especially mannose, on the surface of multiple pathogenic viruses and thus block their ability to attach to cellular receptors. We demonstrated that a lectin from bananas, termed BanLec, is a potent inhibitor of HIV infection. However, BanLec as it is naturally derived from bananas is highly mitogenic, making it undesirable for use as either a systemic therapy or for blocking vaginal transmission of HIV. We overcame this problem by making a single amino acid mutation that totally disrupts mitogenicity while preserving broad-spectrum antiviral activity against HIV, hepatitis C virus, influenza, and all pathogenic coronaviruses, including SARS and MERS. This compound, termed H84T BanLec because the histidine at position 84 has been changed to a threonine, has now been patented in the United States and in several countries in Europe.

a. Swanson, M.D., Winter, H.C., Goldstein, I.J., and Markovitz, D.M. A lectin isolated from bananas is a potent inhibitor of HIV replication. J. Biol. Chem. 2010; 285(12):8646-8655. PMCID: PMC2838287.

b. Ferir, G., Huskens, D., Palmer, K.E., Boudreaux, D.M., Swanson, M.M., Markovitz, D.M., Balzarini, J., and Schols, D. Combinations of griffithsin with other carbohydrate-binding agents (CBAs) demonstrate superior activity against HIV-1, HIV-2 and selected CBA-resistant HIV-1 strains. AIDS Res Hum Retroviruses 2012; 28(11):1513-23. PMCID: PMC3484736.

c. Lectins and Uses Thereof U.S. # 8,865,867, B2 Date of issue: October 21, 2014; also issued in Europe.

d. Swanson, M.D., Boudreaux, D.M., Salmon, S., Chugh, J., Winter, H.C., Meagher, J.L., Andre, S., Murphy, P.V., Oscarson, S., Roy, R., King, S., Kaplan, M.H., Goldstein, I.J., Tarbet, E.B., Hurst, B.L., Smee, D.F., de la Fuente, C., Hoffman, H-H., Xue, Y., Rice, C.M., Schols, D., Garcia, J.V., Stuckey, J.A., Gabius, H-J., Al-Hashimi, H.M., and Markovitz, D.M. Engineering a therapeutic lectin: uncoupling mitogenicity from antiviral activity. Cell 2015; 163:746–758. PMID: 26496612.

Complete List of Published Work in MyBibliography:

http://www.ncbi.nlm.nih.gov/myncbi/browse/collection/48022249/?sort=date&direction=ascending

D. Research Support.

Ongoing Research Support

Rheumatology Research Foundation (RRF) (Markovitz) 07/01/15 – 06/30/18

DEK in the Pathogenesis and Treatment of JIA

The goal of this grant is to understand the role of DEK in juvenile arthritis and to target it in treatment.

Role: PI

Defense Threat Reduction Agency (DTRA) (Markovitz) 08/13/15 – 02/12/18

A Molecularly-Engineered Lectin for Use as a Treatment for Ebola and Marburg Viruses

The goal of this grant is to assess the efficacy of H84T BanLec in the treatment of Ebola and Marburg virus infections.

Role: PI

R01 (Markovitz/Broxmeyer) 07/01/16 – 05/31/20

National Institutes of Health (NIH)

DEK Regulation of Hematopoietic Stem Cell Renewal, Fate, and Hematopoiesis

The goal of this proposal is to study newly-discovered mechanisms by which the DEK protein might mediate blood cell development and successful bone marrow transplantation.

Role: Co-PI

University of Hong Kong (Chan) 12/06/16 – 12/05/18

Efficacy and mechanistic evaluation of banana lectin (BanLec) as a novel pan-coronavirus antiviral agent: in-vitro and ex-vivo evidence

The goal of this project is to develop a biochemically re-engineered lectin and evaluate its antiviral activity against coronaviruses, which are important causes of human and animal diseases.

Role: Co-Investigator

UM Israel Partnership for Research and Education (Reiner/Markovitz) 07/01/17 – 06/30/18

What Makes a Human Brain or What Makes a Brain Human?

The goals of this project are to study the effect of exogenous Np9 expression on neuronal stem cells, and study the consequences of chronic overexpression of Np9 on mouse development.

Role: Co-PI

University of Michigan Mi-Kickstart Award (Markovitz) 01/03/18 – 01/02/19

A molecularly-modified lectin for the treatment of lung cancer

The goal of the project is to test H84T against NSCLC in a mouse model.

Role: PI