Biomedical Sciences Graduate Program(s)
Biomedical Sciences Graduate Programs
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.
Stadnisky, M.D., Xie, X., Coats, E.R., Bullock, T.N. and Brown, M.G. (2011) Self MHC class I -licensed NK cells enhance adaptive CD8 T-cell viral immunity. Blood 117: 5133-5141. PMID: 21436069.
Xie, X., Stadnisky, M.D., Coats, E.R., Rahim, M., Lundgren, A., Xu, W., Makrigiannis, A. and Brown, M.G. (2010) MHC class I Dk expression in hematopoietic and non-hematopoietic cells confers natural killer cell resistance to murine cytomegalovirus. Proc. Natl. Acad. Sci. USA 107:8754-8759. PMID: 20421478.
Stadnisky, M., Manichaikul, A., Lundgren, A.G. and Brown, M.G. (2009) NK gene complex and chromosome 19 loci enhance MHC resistance to murine cytomegalovirus infection. Immunogenetics 61:755-764. PMID: 19820922.
Xie, X., Stadnisky, M. and Brown, M.G. (2009) MHC class I Dk locus and Ly49G2+ NK cells confer H-2k resistance to murine cytomegalovirus. J. Immunol. 182:7163-7171. PMID: 19454713.
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