Gregory A. Viglianti, Ph.D.
Associate Professor of Microbiology
B.A. Lafayette College
Ph.D. University of Minnesota
Mucosal immune responses of the lower female reproductive tract to sexually transmitted pathogenic microorganisms leads to an inflammatory response that enhances the heterosexual transmission of HIV-1. Inflammation is initiated largely by signaling through members of the Toll-like family of innate immune receptors that are activated by pathogen-encoded ligands. This inflammatory response enhances HIV-1 transmission by inducing the recruitment of target immune cells such as Langerhans/dendritic cells (LC/DC), macrophages (MØ)‚ and T lymphocytes to the mucosa and by direct activation of these cells. Recent findings have demonstrated that activation of certain nuclear receptors (NR), including peroxisome proliferator activated receptor (PPAR), liver X receptor (LXR), and glucocorticoid receptor (GR)) potently inhibits TLR-induced inflammatory gene expression in MØ, LC/DC, and epithelial cells. Studies in the Viglianti laboratory are directed toward evaluating the ability of ligand-activated NR to inhibit the mucosal transmission of HIV-1 and to determine the molecular mechanism(s) of how ligand-activated NR inhibit TLR-induced transcription of both HIV-1 and inflammatory cytokine genes.
Autoimmune diseases such as systemic lupus erythematosus (SLE) are characterized by the overproduction of antibodies, many of which recognize ribonucleoprotein and/or chromatin related autoantigens. A common feature of these autoantigens is that they include DNA or RNA. The Viglianti laboratory, in collaboration with Dr. Ann Marshak-Rothstein, is defining the protein and nucleic acid composition of these immunostimulatory autoantigens and determining whether different forms of apoptosis are capable of selectively releasing these autoantigens from cells, thereby making them accessible to autoreactive B cells.
Representative Publications:
1. Viglianti, G.A., C.M. Lau, T.M. Hanley, B.A. Miko, M.J. Schlomchik, and A. Marshak-Rothstein. (2003) Activation of Autoreactive B Cells by dsDNA. Immunity. 19:837-847.
2 . Hanley, T.M., Kiefer, H.L.B., Schnitzler, A., Marcello, J.E., and Viglianti, G.A. (2004) Retinoid-dependent restriction of HIV-1 replication in monocyte/macrophages. J. Virology. 78:2819-2830.
3. Marshak-Rothstein, A., Busconi, L., Lau, C.M., Tabor, A.S., Leadbetter, E.A., Akira, S., Krieg, A.M., Lipford, G.B., Viglianti, G.A., and Rifkin, I.R. (2004) Comparison of CpG s-ODNs, Chromatin Immune Complexes, and dsDNA Fragment Immune Complexes in the TLR9-dependent Activation of Rheumatoid Factor B Cells. J. Endotoxin Res. 10:247-251.
4. Kiefer, H.L.B., Hanley, T.M., Marcello, J.E., Karthik, A.G. and Viglianti, G. A. (2004) Retinoic Acid Inhibition of Chromatin Remodeling at the Human Immunodeficiency Virus Type 1 Promoter: Uncoupling of Histone Acetylation and Chromatin Remodeling. J. Biol. Chem. 279:43604-43613.
5. Marshak-Rothstein, A., Busconi, L., Rifkin, I.R., and Viglianti, G.A. (2004) The stimulation of Toll-like receptors by nuclear antigens: a link between apoptosis and autoimmunity In: Pisetsky, D.S. ed. Rheumatic Disease Clinics of North America: Apoptosis in the Rheumatic Diseases, Saunders, Philadelphia, PA. Vol. 30 (3) pp 559-574.
6. Rifkin, I.R., Leadbetter, E.A., Busconi, L., Viglianti, G., and Marshak-Rothstein, A. (2005) Toll-like Receptors, Endogenous Ligands, and Systemic Autoimmune Disease. Immunological Reviews 204: 27-42.
7. Lau, C.M., Broughton, C., Tabor, A.S., Akira, S., Mamula, M., Christensen, S.R., Shlomchik, M.J., Viglianti, G.A., Rifkin, I.R., and Marshak-Rothstein, A. (2005) RNA-Associated Autoantigens Activate B Cells by Combined BCR/Toll-like Receptor 7 Engagement. J. Exp. Med. 202: 1171-1177.
8. Busconi, L., Lau, C.M., Tabor, A.S., Uccellini, M.B., Ruhe, Z., Akira, S., Viglianti, G.A., Rifkin, I.R., and Marshak-Rothstein, A. (2006) DNA and RNA autoantigens as autoadjuvants. J. Endotoxin Res. 12:379-384.
9. Uccellini,M.B., Busconi, L., Green, N.M., Busto, P., Christensen, S.R., Shlomchik, M.J., Marshak-Rothstein, A., and Viglianti, G.A. (2008) Autoreactive B Cells Discriminate CpG-rich and CpG-poor DNA and This Response is Modulated by IFN-a. J. of Immunology 181:5875-5884.
10. Yasuda, K., Richez, C., Uccellini, M.B., Richards, R.J., Akira, S., Monestier, M., Corley, R.B., Viglianti, G.A., Marshak-Rothstein, A., and Rifkin,I.R. (2009) Requirement for DNA CpG Content in TLR9-dependent Dendritic Cell Activation Induced by DNA-containing Immune Complexes. J. Immunology 183:3109-3117. (PMID: 19648272)
11. Hanley, T.M., Puryear, W.B., Gummuluru, S., and Viglianti, G.A. (2010) PPARg and LXR Signaling Inhibit Dendritic Cell-mediated HIV-1 Capture and trans-infection. PLoS Pathog 6(7): e1000981.
12. Avalos, A.M., Uccellini, M.B., Lenert, P., Viglianti, G., and Marshak-Rothstein, A. (In Press, Eur. J. Immunol.) FcgRIIB Regulation of BCR/TLR- Dependent Autoreactive B Cell Responses.
