Michael Brown, PhD Lab

PRIMARY APPOINTMENT:

Professor, Medicine: Nephrology

CONTACT:

PO Box 801386
MR6, Rm 2714A
Charlottesville, Virginia 22908
Telephone: 434-924-5106
Fax: 434-924-1221
Email: mgbrown@virginia.edu

EDUCATION AND TRAINING:

• 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

FUNDED PROJECTS:

• NIH/NAIAD 5R01AI050072-17 (Molecular study mouse virus resistance mechanisms)
• NIH/NAIAD 1R21AI141943-01A1 (TNFRSF Genetics Related to NK Cell Control of MCMV)

RESEARCH AREAS:

Cancer Immunology, Genetics of Virus Immunity, Host Defense Mechanisms, Host-Pathogen Interaction, Natural Killer (NK) Cells, Role of NK Cells in Non-Small Cell Lung Cancer (NSCLC).

RESEARCH SUMMARY:

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.

SELECTED PUBLICATIONS:

1. Shi L, Li K, Guo Y, Banerjee A, Wang Q, Lorenz UM, Parlak M, Sullivan LC, Onyema OO, Arefanian S, Stelow EB, Brautigan DL, Bullock TNJ, Brown MG, Krupnick AS, Modulation of NKG2D, NKp46, and Ly49C/I facilitates natural killer cell-mediated control of lung cancer., 2018; Proceedings of the National Academy of Sciences of the United States of America. 115(46) 11808-11813. PMID: 30381460 | PMCID: PMC6243255
2. Brown MG, Gamache A, Nash WT, Cronk J, Natural selection for killer receptors and their MHC class I ligands: In pursuit of gene pairs that fit well in tandem., 2018; Journal of leukocyte biology. () . PMID: 30500089
3. Nash WT, Gillespie AL, Brown MG, Murine Cytomegalovirus Disrupts Splenic Dendritic Cell Subsets via Type I Interferon-Dependent and -Independent Mechanisms., 2017; Frontiers in immunology. 8() 251. PMID: 28337202 | PMCID: PMC5343017
4. Gillespie A, Lee H, Robertson C, Cabot M, Brown MG, Genome-Wide Exome Analysis of Cmv5-Disparate Mouse Strains that Differ in Host Resistance to Murine Cytomegalovirus Infection., 2017; G3 (Bethesda, Md.). 7(6) 1979-1984. PMID: 28450376 | PMCID: PMC5473773
5. Gillespie AL, Teoh J, Lee H, Prince J, Stadnisky MD, Anderson M, Nash W, Rival C, Wei H, Gamache A, Farber CR, Tung K, Brown MG, Genomic Modifiers of Natural Killer Cells, Immune Responsiveness and Lymphoid Tissue Remodeling Together Increase Host Resistance to Viral Infection., 2016; PLoS pathogens. 12(2) e1005419. PMID: 26845690 | PMCID: PMC4742223
6. Krueger PD, Narayanan S, Surette FA, Brown MG, Sung SJ, Hahn YS, Murine liver-resident group 1 innate lymphoid cells regulate optimal priming of anti-viral CD8+ T cells., 2016; Journal of leukocyte biology. 101(1) 329-338. PMID: 27493244
7. Teoh JJ, Gamache AE, Gillespie AL, Stadnisky MD, Yagita H, Bullock TN, Brown MG, Acute Virus Control Mediated by Licensed NK Cells Sets Primary CD8+ T Cell Dependence on CD27 Costimulation., 2016; Journal of immunology (Baltimore, Md. : 1950). 197(11) 4360-4370. PMID: 27798162 | PMCID: PMC5123769
8. Brown MG, Erickson LD, Editorial: NK cell reaping of Tfh cells: reckless slaughter or sensible pruning?, 2015; Journal of leukocyte biology. 98(2) 139-42. PMID: 26048981
9. Nash WT, Teoh J, Wei H, Gamache A, Brown MG, Know Thyself: NK-Cell Inhibitory Receptors Prompt Self-Tolerance, Education, and Viral Control., 2014; Frontiers in immunology. 5() 175. PMID: 24795719 | PMCID: PMC3997006
10. Wei H, Nash WT, Makrigiannis AP, Brown MG, Impaired NK-cell education diminishes resistance to murine CMV infection., 2014; European journal of immunology. () . PMID: 25187217 | PMCID: PMC4233007
11. Prince J, Lundgren A, Stadnisky MD, Nash WT, Beeber A, Turner SD, Brown MG, Multiparametric analysis of host response to murine cytomegalovirus in MHC class I-disparate mice reveals primacy of Dk-licensed Ly49G2+ NK cells in viral control., 2013; Journal of immunology (Baltimore, Md. : 1950). 191(9) 4709-19. PMID: 24068668 | PMCID: PMC3820117
12. Lundgren A, Kim S, Stadnisky MD, Brown MG, Rapid discrimination of MHC class I and killer cell lectin-like receptor allele variants by high-resolution melt analysis., 2012; Immunogenetics. 64(8) 633-40. PMID: 22752191 | PMCID: PMC3596047
13. Ge Y, Brown MG, Wang H, Fu SM, Genetic approach to study lupus glomerulonephritis., 2012; Methods in molecular biology (Clifton, N.J.). 900() 271-90. PMID: 22933074 | PMCID: PMC3873643
14. Stadnisky MD, Xie X, Coats ER, Bullock TN, Brown MG, Self MHC class I-licensed NK cells enhance adaptive CD8 T-cell viral immunity., 2011; Blood. 117(19) 5133-41. PMID: 21436069 | PMCID: PMC3109538
15. Carroll VA, Lundgren A, Wei H, Sainz S, Tung KS, Brown MG, Natural killer cells regulate murine cytomegalovirus-induced sialadenitis and salivary gland disease., 2011; Journal of virology. 86(4) 2132-42. PMID: 22156514 | PMCID: PMC3302420
16. Xie X, Stadnisky MD, Coats ER, Ahmed Rahim MM, Lundgren A, Xu W, Makrigiannis AP, Brown MG, MHC class I D(k) expression in hematopoietic and nonhematopoietic cells confers natural killer cell resistance to murine cytomegalovirus., 2010; Proceedings of the National Academy of Sciences of the United States of America. 107(19) 8754-9. PMID: 20421478 | PMCID: PMC2889336
17. Lassen MG, Lukens JR, Dolina JS, Brown MG, Hahn YS, Intrahepatic IL-10 maintains NKG2A+Ly49- liver NK cells in a functionally hyporesponsive state., 2010; Journal of immunology (Baltimore, Md. : 1950). 184(5) 2693-701. PMID: 20124099 | PMCID: PMC2885840
18. Stadnisky MD, Manichaikul A, Lundgren AG, Brown MG, NK gene complex and chromosome 19 loci enhance MHC resistance to murine cytomegalovirus infection., 2009; Immunogenetics. 61(11) 755-64. PMID: 19820922 | PMCID: PMC2880465
19. Xie X, Stadnisky MD, Brown MG, MHC class I Dk locus and Ly49G2+ NK cells confer H-2k resistance to murine cytomegalovirus., 2009; Journal of immunology (Baltimore, Md. : 1950). 182(11) 7163-71. PMID: 19454713 | PMCID: PMC2730597
20. Rodriguez MR, Lundgren A, Sabastian P, Li Q, Churchill G, Brown MG, A Cmv2 QTL on chromosome X affects MCMV resistance in New Zealand male mice., 2009; Mammalian genome : official journal of the International Mammalian Genome Society. 20(7) 414-23. PMID: 19641964 | PMCID: PMC2767104
21. Brown MG, Scalzo AA, NK gene complex dynamics and selection for NK cell receptors., 2008; Seminars in immunology. 20(6) 361-8. PMID: 18640056 | PMCID: PMC2646111
22. Li L, Huang L, Sung SS, Lobo PI, Brown MG, Gregg RK, Engelhard VH, Okusa MD, NKT cell activation mediates neutrophil IFN-gamma production and renal ischemia-reperfusion injury., 2007; Journal of immunology (Baltimore, Md. : 1950). 178(9) 5899-911. PMID: 17442974
23. Xie X, Dighe A, Clark P, Sabastian P, Buss S, Brown MG, Deficient major histocompatibility complex-linked innate murine cytomegalovirus immunity in MA/My.L-H2b mice and viral downregulation of H-2k class I proteins., 2006; Journal of virology. 81(1) 229-36. PMID: 17050600 | PMCID: PMC1797260
24. Scalzo AA, Manzur M, Forbes CA, Brown MG, Shellam GR, NK gene complex haplotype variability and host resistance alleles to murine cytomegalovirus in wild mouse populations., 2005; Immunology and cell biology. 83(2) 144-9. PMID: 15748210
25. Dighe A, Rodriguez M, Sabastian P, Xie X, McVoy M, Brown MG, Requisite H2k role in NK cell-mediated resistance in acute murine cytomegalovirus-infected MA/My mice., 2005; Journal of immunology (Baltimore, Md. : 1950). 175(10) 6820-8. PMID: 16272339
26. Rodriguez M, Sabastian P, Clark P, Brown MG, Cmv1-independent antiviral role of NK cells revealed in murine cytomegalovirus-infected New Zealand White mice., 2004; Journal of immunology (Baltimore, Md. : 1950). 173(10) 6312-8. PMID: 15528370
27. Wheat RL, Clark PY, Brown MG, Quantitative measurement of infectious murine cytomegalovirus genomes in real-time PCR., 2003; Journal of virological methods. 112(1) 107-13. PMID: 12951218
28. Scalzo AA, Wheat R, Dubbelde C, Stone L, Clark P, Du Y, Dong N, Stoll J, Yokoyama WM, Brown MG, Molecular genetic characterization of the distal NKC recombination hotspot and putative murine CMV resistance control locus., 2003; Immunogenetics. 55(6) 370-8. PMID: 12920489
29. Brown MG, Scalzo AA, Stone LR, Clark PY, Du Y, Palanca B, Yokoyama WM, Natural killer gene complex (Nkc) allelic variability in inbred mice: evidence for Nkc haplotypes., 2001; Immunogenetics. 53(7) 584-91. PMID: 11685471
30. Brown MG, Dokun AO, Heusel JW, Smith HR, Beckman DL, Blattenberger EA, Dubbelde CE, Stone LR, Scalzo AA, Yokoyama WM, Vital involvement of a natural killer cell activation receptor in resistance to viral infection., 2001; Science (New York, N.Y.). 292(5518) 934-7. PMID: 11340207
31. Brown MG, Zhang J, Du Y, Stoll J, Yokoyama WM, Scalzo AA, Localization on a physical map of the NKC-linked Cmv1 locus between Ly49b and the Prp gene cluster on mouse chromosome 6., 1999; Journal of immunology (Baltimore, Md. : 1950). 163(4) 1991-9. PMID: 10438936
32. Scalzo AA, Brown MG, Chu DT, Heusel JW, Yokoyama WM, Forbes CA, Development of intra-natural killer complex (NKC) recombinant and congenic mouse strains for mapping and functional analysis of NK cell regulatory loci., 1999; Immunogenetics. 49(3) 238-41. PMID: 9914339
33. Ho EL, Heusel JW, Brown MG, Matsumoto K, Scalzo AA, Yokoyama WM, Murine Nkg2d and Cd94 are clustered within the natural killer complex and are expressed independently in natural killer cells., 1998; Proceedings of the National Academy of Sciences of the United States of America. 95(11) 6320-5. PMID: 9600963 | PMCID: PMC27675
34. Yokoyama WM, Matsumoto K, Scalzo AA, Brown MG, Molecular genetics of the natural killer gene complex and innate immunity., 1997; Biochemical Society transactions. 25(2) 691-5. PMID: 9191184
35. Brown MG, Scalzo AA, Matsumoto K, Yokoyama WM, The natural killer gene complex: a genetic basis for understanding natural killer cell function and innate immunity., 1997; Immunological reviews. 155() 53-65. PMID: 9059882
36. Forbes CA, Brown MG, Cho R, Shellam GR, Yokoyama WM, Scalzo AA, The Cmv1 host resistance locus is closely linked to the Ly49 multigene family within the natural killer cell gene complex on mouse chromosome 6., 1997; Genomics. 41(3) 406-13. PMID: 9169139
37. Brown MG, Fulmek S, Matsumoto K, Cho R, Lyons PA, Levy ER, Scalzo AA, Yokoyama WM, A 2-Mb YAC contig and physical map of the natural killer gene complex on mouse chromosome 6., 1997; Genomics. 42(1) 16-25. PMID: 9177771
38. Driscoll J, Brown MG, Finley D, Monaco JJ, MHC-linked LMP gene products specifically alter peptidase activities of the proteasome., 1993; Nature. 365(6443) 262-4. PMID: 8371781
39. Brown MG, Driscoll J, Monaco JJ, MHC-linked low-molecular mass polypeptide subunits define distinct subsets of proteasomes. Implications for divergent function among distinct proteasome subsets., 1993; Journal of immunology (Baltimore, Md. : 1950). 151(3) 1193-204. PMID: 8335924
40. Cho S, Attaya M, Brown MG, Monaco JJ, A cluster of transcribed sequences between the Pb and Ob genes of the murine major histocompatibility complex., 1991; Proceedings of the National Academy of Sciences of the United States of America. 88(12) 5197-201. PMID: 1711220 | PMCID: PMC51839
41. Brown MG, Driscoll J, Monaco JJ, Structural and serological similarity of MHC-linked LMP and proteasome (multicatalytic proteinase) complexes., 1991; Nature. 353(6342) 355-7. PMID: 1922341