Michael G. Brown

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Primary Appointment

Professor, Medicine- Nephrology

Education

  • BS, Biochemistry, Virginia Tech University
  • PhD, Immunology, Medical College of Virginia, Virginia Commonwealth University
  • Postdoc, Immunology, Mount Sinai School of Medicine
  • Postdoc, Immunology, Washington University

Research Disciplines

Bioinformatics and Genomics, Biotechnology, Genetics, Immunology, Infectious Diseases/Biodefense, Microbiology

Research Interests

Natural Killer Cells, Viral Immunity, Genetic basis of host resistance to viral infection, Tumor immunity, Immune cell regulation

Research Description

A main goal of research in the Brown Lab centers on the genetics of host resistance to viral infection, and the role of natural killer (NK) cells in viral immunity. We aim to understand (1) how genetic variation shapes both innate and adaptive immune cell features, and how these differences further affect immune cells needed to detect and clear viral pathogens; (2) how NK cell effector function is acquired and regulated by both genetic and environmental influences; and (3) how NK responses to immune stimulation can specifically regulate adaptive immune outcomes.
We have learned that the major histocompatibility complex (MHC) exerts substantial control over NK cells, and we have developed several informative mouse models to explore this effect in much greater depth. We found that MHC class I-dependent education (also referred to as licensing), affects the capacity of NK cells to mediate virus-specific clearance, in addition to its effect on NK cell functionality. We hypothesize that licensing impacts NK-mediated responsiveness to cancer cells, as well. While the molecular basis of licensing remains poorly defined, the model systems and resources now developed in the lab provide an outstanding way to explore the basis and vital roles of NK cells in viral or tumor immunity.

Personal Statement

My research program centers on the genetics of host resistance to viral infection, and the role of NK cells in viral immunity. This stems from my early work with MHC-linked proteasome subunits and MHC class I antigen processing. My primary goals aim to understand (1) how genetic variation shapes both innate and adaptive immune cell features, and how these differences further affect immune cells needed to detect and clear viral pathogens; (2) how NK cell effector function is acquired and regulated by both genetic and environmental influences; and (3) how NK responses to immune stimulation can specifically regulate adaptive immune outcomes.
We have learned that the MHC exerts substantial control over NK cells, and we have developed several informative mouse models to examine this effect in greater depth. We found that MHC class I-dependent education (also referred to as licensing), affects the capacity of NK cells to mediate virus-specific clearance, in addition to its effect on NK functionality. We hypothesize that licensing impacts NK-mediated responsiveness to cancer cells. While the molecular basis of licensing is poorly defined, the model systems and resources that we have acquired and developed allow us to probe how NK cells recognize and mediate lysis of infected or malignant target cells.

Training

  • Biodefense & Infectious Diseases Short-Term Training to Increase Diversity in Biomedical Sciences
  • Biotechnology Training Grant
  • Interdisciplinary Training Program in Immunology

Selected Publications

2022

Cronk, J. M., Dziewulska, K. H., Puchalski, P., Crittenden, R. B., Hammarskjöld, M. -L., & Brown, M. G. (2022). Altered-Self MHC Class I Sensing via Functionally Disparate Paired NK Cell Receptors Counters Murine Cytomegalovirus gp34-Mediated Immune Evasion.. Journal of immunology (Baltimore, Md. : 1950), 209(8), 1545-1554. doi:10.4049/jimmunol.2200441

Nozaki, K., Maltez, V. I., Rayamajhi, M., Tubbs, A. L., Mitchell, J. E., Lacey, C. A., . . . Miao, E. A. (2022). Caspase-7 activates ASM to repair gasdermin and perforin pores. NATURE, 606(7916), 960-+. doi:10.1038/s41586-022-04825-8

2021

Cronk, J. M., Fafoutis, E., & Brown, M. G. (2021). Licensing Natural Killers for Antiviral Immunity. PATHOGENS, 10(7). doi:10.3390/pathogens10070908

2019

Gamache, A., Cronk, J. M., Nash, W. T., Puchalski, P., Gillespie, A., Wei, H., . . . Brown, M. G. (2019). Ly49R activation receptor drives self-MHC-educated NK cell immunity against cytomegalovirus infection. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 116(52), 26768-26778. doi:10.1073/pnas.1913064117

Brown, M. G., Gamache, A., Nash, W. T., & Cronk, J. (2019). Natural selection for killer receptors and their MHC class I ligands: In pursuit of gene pairs that fit well in tandem. JOURNAL OF LEUKOCYTE BIOLOGY, 105(3), 489-495. doi:10.1002/JLB.2RI0818-315R

2018

Shi, L., Li, K., Guo, Y., Banerjee, A., Wang, Q., Lorenz, U. M., . . . Krupnick, A. S. (2018). Modulation of NKG2D, NKp46, and Ly49C/I facilitates natural killer cell-mediated control of lung cancer. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 115(46), 11808-11813. doi:10.1073/pnas.1804931115

2017

Brown, M. G., & Gamache, A. (2017). Editorial: On matters of maturity, self-control, and responsiveness: inhibitory NK receptors in the driver's seat?. JOURNAL OF LEUKOCYTE BIOLOGY, 102(6), 1281-1284. doi:10.1189/jlb.1CE0717-280RR

Gillespie, A., Lee, H., Robertson, C., Cabot, M., & Brown, M. G. (2017). Genome-Wide Exome Analysis of Cmv5-Disparate Mouse Strains that Differ in Host Resistance to Murine Cytomegalovirus Infection. G3-GENES GENOMES GENETICS, 7(6), 1979-1984. doi:10.1534/g3.117.042531

Nash, W. T., Gillespie, A. L., & Brown, M. G. (2017). Murine cytomegalovirus Disrupts splenic Dendritic cell subsets via Type I Interferon-Dependent and -Independent Mechanisms. FRONTIERS IN IMMUNOLOGY, 8. doi:10.3389/fimmu.2017.00251

Krueger, P. D., Narayanan, S., Surette, F. A., Brown, M. G., Sung, S. -S. J., & Hahn, Y. S. (2017). Murine liver-resident group 1 innate lymphoid cells regulate optimal priming of anti-viral CD8(+) T cells. JOURNAL OF LEUKOCYTE BIOLOGY, 101(1), 329-338. doi:10.1189/jlb.3A0516-225R

2016

Teoh, J. J., Gamache, A. E., Gillespie, A. L., Stadnisky, M. D., Yagita, H., Bullock, T. N. J., & Brown, M. G. (2016). Acute Virus Control Mediated by Licensed NK Cells Sets Primary CD8+ T Cell Dependence on CD27 Costimulation.. Journal of immunology (Baltimore, Md. : 1950), 197(11), 4360-4370. doi:10.4049/jimmunol.1601049

Gillespie, A. L., Teoh, J., Lee, H., Prince, J., Stadnisky, M. D., Anderson, M., . . . Brown, M. G. (2016). Genomic Modifiers of Natural Killer Cells, Immune Responsiveness and Lymphoid Tissue Remodeling Together Increase Host Resistance to Viral Infection. PLOS PATHOGENS, 12(2). doi:10.1371/journal.ppat.1005419

2015

Brown, M. G., & Erickson, L. D. (2015). Editorial: NK cell reaping of Tfh cells: reckless slaughter or sensible pruning?. JOURNAL OF LEUKOCYTE BIOLOGY, 98(2), 139-142. doi:10.1189/jlb.4CE0415-175R

2014

Wei, H., Nash, W. T., Makrigiannis, A. P., & Brown, M. G. (2014). Impaired NK-cell education diminishes resistance to murine CMV infection. EUROPEAN JOURNAL OF IMMUNOLOGY, 44(11), 3273-3282. doi:10.1002/eji.201444800

Nash, W. T., Teoh, J., Wei, H., Gamache, A., & Brown, M. G. (2014). Know thyself: NK-cel innibitory receptors prompt self-tolerance, education, and viral control. FRONTIERS IN IMMUNOLOGY, 5, 1-12. doi:10.3389/fimmu.2014.00175

2013

Prince, J., Lundgren, A., Stadnisky, M. D., Nash, W. T., Beeber, A., Turner, S. D., & Brown, M. G. (2013). Multiparametric Analysis of Host Response to Murine Cytomegalovirus in MHC Class I-Disparate Mice Reveals Primacy of D-k-Licensed Ly49G(2)(+) NK Cells in Viral Control. JOURNAL OF IMMUNOLOGY, 191(9), 4709-4719. doi:10.4049/jimmunol.1301388

2012

Lundgren, A., Kim, S., Stadnisky, M. D., & Brown, M. G. (2012). Rapid discrimination of MHC class I and killer cell lectin-like receptor allele variants by high-resolution melt analysis. IMMUNOGENETICS, 64(8), 633-640. doi:10.1007/s00251-012-0630-4

Carroll, V. A., Lundgren, A., Wei, H., Sainz, S., Tung, K. S., & Brown, M. G. (2012). Natural Killer Cells Regulate Murine Cytomegalovirus-Induced Sialadenitis and Salivary Gland Disease. JOURNAL OF VIROLOGY, 86(4), 2132-2142. doi:10.1128/JVI.06898-11

Ge, Y., Brown, M. G., Wang, H., & Fu, S. M. (2012). Genetic approach to study lupus glomerulonephritis.. Methods in molecular biology (Clifton, N.J.), 900, 271-290. doi:10.1007/978-1-60761-720-4_13

2011

Stadnisky, M. D., Xie, X., Coats, E. R., Bullock, T. N., & Brown, M. G. (2011). Self MHC class I-licensed NK cells enhance adaptive CD8 T-cell viral immunity. BLOOD, 117(19), 5133-5141. doi:10.1182/blood-2010-12-324632

2010

Xie, X., Stadnisky, M. D., Coats, E. R., Rahim, M. M. A., Lundgren, A., Xu, W., . . . Brown, M. G. (2010). MHC class I D-k expression in hematopoietic and nonhematopoietic cells confers natural killer cell resistance to murine cytomegalovirus. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 107(19), 8754-8759. doi:10.1073/pnas.0913126107

Lassen, M. G., Lukens, J. R., Dolina, J. S., Brown, M. G., & Hahn, Y. S. (2010). Intrahepatic IL-10 Maintains NKG2A(+)Ly49(-) Liver NK Cells in a Functionally Hyporesponsive State. JOURNAL OF IMMUNOLOGY, 184(5), 2693-2701. doi:10.4049/jimmunol.0901362