Associate Professor of Microbiology and of Immunology
Phone:(206) 616-4285, (206) 221-5693
Office Location: Health Sciences, J-287A
Campus Box: 357735
Michael Lagunoff received his bachelors degree in Chemistry from Oberlin College and his Ph.D. in Virology from the University of Chicago. He went on to do his post-doctoral training at the University of California, San Francisco where he began work on the molecular biology of Kaposi's Sarcoma-associated Herpesvirus (KSHV).
KSHV is the etiologic agent of Kaposi's Sarcoma (KS), a highly vascularized hyperplasia that is the most common tumor in AIDS patients and is currently the most commonly reported tumor in regions of Africa. The main tumor cell of KS is the spindle cell, a cell of endothelial origin. The laboratory is interested in how the virus alters the host endothelial cells to induce tumors. The main focus is to understand how the activation of cellular signal transduction alters endothelial cells for the benefit of viral latency and leads to oncogenesis.
The highly vascularized nature of the KS tumor led us to examine if latent KSHV infection can directly induce new blood vessel formation or angiogenesis. The lab found that KSHV induces angiogenic phenotypes upon infection of endothelial cells in culture and requires integrin signaling for this effect. Interestingly, we found that KSHV infection of blood endothelial cells reprograms them to differentiate into lymphatic endothelium and showed that STAT3 activation of AKT is required for this reprogramming. This indicates that lymphangiogenesis may also be of critical importance for KSHV induced tumors. Work on mapping the cellular and viral mechanisms of KSHV induced endothelial cell differentiation and the functional outcomes of differentiation for the virus is ongoing.
Another main focus of the lab is virally induced alteration of host cell metabolism. While viruses do not inherently have metabolism, infection can dramatically alter the host cell metabolism for the benefit of the virus. We found that KSHV induces the Warburg effect, an effect common to almost all tumor cells. The Warburg effect is the induction of glycolysis and a decrease in oxidative phosphorylation. We believe that induction of the Warburg effect allows rapid adaptation of latently infected cells to tumor environments allowing the expansion of latency. Through examination of global changes in metabolic pathways induced by KSHV we found that KSHV alters many other metabolic pathways. KSHV induced metabolic changes in the host cell are required for the survival of latently infected cells. Therefore, these pathologic changes in metabolism may provide novel therapeutic targets for KSHV latency. Further work mapping the changes in cellular metabolism, the carbon utilization of infected cells and the signal transduction pathways necessary for virus induced alterations in metabolism is ongoing.
Selected recent publications:
Punjabi, A.S., Carroll, P.A., Chen, L. and M. Lagunoff. 2007. Persistent activation of STAT3 by latent KSHV infection of endothelial cells. 81:2449-2458. Journal of Virology.
Orr, M.T., Mathis, M.A., Lagunoff, M., Sacks, J.A. and Wilson C.B. 2007. CD8 T cell control of HSV reactivation from latency is abrogated by viral inhibition of MHC class I. Cell Host and Microbe 2:172-80.
Morris, V.A., Punjabi, A.S. and Lagunoff, M. 2008. Activation of AKT through the gp130 receptor is required for KSHV induced lymphatic reprogramming of endothelial cells. Journal of Virology. 82:8771-79
Delgado, T, Carroll, P.A., Punjabi, A.S., Margineantu, D, Hockenbery, D and Lagunoff, M. 2010. Induction of the Warburg effect by Kaposi's Sarcoma Herpesvirus is required for the maintenance of latently infected endothelial cells. PNAS 107:10696-701.
DiMaio, T, Gutierrez K.D. and Lagunoff, M. 2011 Latent KSHV infection of Endothelial cells induces Integrin Beta3 to Activate angiogenic phenotypes. PLoS Pathogens 7(12): e1002424. doi:10.1371
Morris, V.A., Punjabi, A.S., Wells, R.C., Wittkopp, C.J., Vart, R, and Lagunoff, M. 2012. The KSHV viral IL-6 homolog is sufficient to induce blood to lymphatic endothelial cell differentiation. Virology, 428:112-120
Delgado, T, Sanchez, E, Camarda, R and Lagunoff M. 2012. Global metabolic profiling of infection by an oncogenic virus: KSHV induces and requires lipogenesis for survival of latent infection. PLoS Pathogens 8(8): e1002866. doi:10.1371.