Michael G. Brown, PhD
Graduate School: Virginia Commonwealth University
Primary Appointment: Professor, Medicine, Nephrology
NK Cells and Viral Immunity
Email Address: email@example.com
Immunology, Molecular Biology and Genetics: Research in the Brown Laboratory is centered on molecular and cellular mechanisms of innate immunity and antiviral host defenses. We have applied classical genetic analysis strategies to examine how genetic diversity affects host virus resistance or susceptibility traits in common laboratory strains of mice. Major alleles that contribute to strain-dependent differences in virus resistance and/or immune responsiveness will undoubtedly enhance our understanding of the immune system, which could also lead to identification of new and beneficial targets of immune therapy. Two major research project areas established in the lab are detailed below.
Virus Immunity Research - Microbiology, Immunology and Infectious Disease: Natural killer (NK) cells are known for killing malignant or virus infected cells. NK cell-mediated immunity against a wide range of viral pathogens, including RNA and DNA viruses, highlights their prominent antiviral role in the body. In previous work, we found that Ly49H activation receptors expressed on NK cells in C57BL/6 mice were needed for resistance to murine cytomegalovirus (MCMV) infection. This is because Ly49H specifically binds to m157, an MCMV encoded protein with MHC class I protein similarity. Thus, Ly49H+ NK cells can target efficient MCMV recognition and virus control.
In our recent genetic studies, Ly49H-independent virus resistance factors were also uncovered. Virus resistance effects have been mapped to MHC and non-MHC chromosome locations; their individual and combined impact on NK cell-mediated virus immunity is under investigation. Refined genetic mapping for MHC-dependent (H-2k) MCMV resistance has led to the class I D locus and the finding that NK cells confer H-2k resistance. Ongoing studies aim to examine molecular and cellular mechanisms associated with MHC and non-MHC early resistance to virus infection. The effect of early and efficient NK-mediated virus resistance on virus-specific immunity, inflammation, tissue damage and later virus clearance is an active area of research.
Viral Pathogenesis Research - Immunity and Inflammation: MCMV causes marked sialadenitis in immune competent systemic lupus erythematosus (SLE-) prone NZM2328 mice shortly after infection, coincident with high-level virus in salivary gland. Generally diffuse inflammatory infiltrates in salivary and lacrimal glands tend to transition toward focal inflammatory lesions in NZM2328 females after MCMV latency becomes established. Ongoing studies in the lab aim to investigate molecular and cellular mechanisms governing virus induced disease features, including inflammation and glandular dysfunction. Our recent findings suggest that MCMV is a useful tool to examine virus-induced inflammation and tissue damage, which can also be used to model human Sjögren’s Syndrome (SS) and SS secondary to virus infection.
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. J Immunol. 2013 Nov 1;191(9):4709-19. doi: 10.4049/jimmunol.1301388. Epub 2013 Sep 25. PubMed PMID: 24068668
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. Immunogenetics. 2012 Aug;64(8):633-40. doi: 10.1007/s00251-012-0630-4. Epub 2012 Jul 1. PubMed PMID: 22752191
Carroll VA, Lundgren A, Wei H, Sainz S, Tung KS, Brown MG. Natural killer cells regulate murine cytomegalovirus-induced sialadenitis and salivary gland disease. J Virol. 2012 Feb;86(4):2132-42. doi: 10.1128/JVI.06898-11. Epub 2011 Dec 7. PubMed PMID: 22156514
Ge Y, Brown MG, Wang H, Fu SM. Genetic approach to study lupus glomerulonephritis. Methods Mol Biol. 2012;900:271-90. doi: 10.1007/978-1-60761-720-4_13. PubMed PMID: 22933074
Stadnisky MD, Xie X, Coats ER, Bullock TN, Brown MG. Self MHC class I-licensed NK cells enhance adaptive CD8 T-cell viral immunity. Blood. 2011 May 12;117(19):5133-41. doi: 10.1182/blood-2010-12-324632. Epub 2011 Mar 23. PubMed PMID: 21436069
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. Proc Natl Acad Sci U S A. 2010 May 11;107(19):8754-9. doi: 10.1073/pnas.0913126107. Epub 2010 Apr 26. PubMed PMID: 20421478
Lassen MG, Lukens JR, Dolina JS, Brown MG, Hahn YS. Intrahepatic IL-10 maintains NKG2A+Ly49- liver NK cells in a functionally hyporesponsive state. J Immunol. 2010 Mar 1;184(5):2693-701. doi: 10.4049/jimmunol.0901362. Epub 2010 Feb 1. PubMed PMID: 20124099
Stadnisky MD, Manichaikul A, Lundgren AG, Brown MG. NK gene complex and chromosome 19 loci enhance MHC resistance to murine cytomegalovirus infection. Immunogenetics. 2009 Dec;61(11-12):755-64. doi: 10.1007/s00251-009-0400-0. Epub 2010 Jan 5. PubMed PMID: 19820922
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. Mamm Genome. 2009 Jul;20(7):414-23. doi: 10.1007/s00335-009-9203-8. Epub 2009 Jul 30. PubMed PMID: 19641964
Xie X, Stadnisky MD, Brown MG. MHC class I Dk locus and Ly49G2+ NK cells confer H-2k resistance to murine cytomegalovirus. J Immunol. 2009 Jun 1;182(11):7163-71. doi: 10.4049/jimmunol.0803933. PubMed PMID: 19454713; PubMed Central PMCID: PMC273059
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