Staff Biography
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Andrew D. Yurochko, PH.DAssociate Professor Center for Molecular and Tumor Virology, |
ContactPhone: (318) 675-8332 Team Membership |
Education / Research / Publications
Education / Professional Experience
Postdoctoral Study, University of North Carolina at Chapel Hill School of Medicine
Ph.D., Immunology - Macrophage Biology, 1990, Virginia Tech
B.S., Biochemistry and Biology, 1985, Virginia Tech
Research Interest
Cytomegalovirus Activation of Cellular Genes and the Mechanisms of Viral Dissemination
(I) One of the hallmarks of human cytomegalovirus (HCMV) infection is a dramatic increase in cellular activation, which plays a role in the pathogenesis of the severe diseases associated with HCMV infection. To investigate this process, we are studying the upregulation of cellular transcription factors following HCMV infection. We showed that HCMV infection resulted in an increase in cellular transcription factors needed for the initiation and maintenance of the viral life cycle. Specifically, we showed that viral binding was responsible for this induction and that the HCMV immediate-early genes in conjunction with cellular factors were instrumental in activating the cell. Our future goals include the dissection of the players leading from the first step of viral-mediated cellular activation, viral binding, to the initiation of the viral life cycle.
(II) Secondly, we are examining the events that occur in human monocytes following HCMV infection because of the critical role these cells play in viral dissemination and disease pathogenesis. We begun addressing from a molecular standpoint, how viral infection of monocytes generates a sufficient signal to upregulate cellular transcription factors, which in turn forces the activated monocytes to migrate from the blood into peripheral tissues and differentiate into macrophages, allowing viral replication in host tissue and viral spread throughout the body. We showed that HCMV specifically induces monocyte-to-macrophage differentiation and that these viral-induced macrophages become permissive for viral replication, suggesting that HCMV utilizes a novel mechanism for viral dissemination. Future studies include the examination of the mechanisms responsible for the viral-directed differentiation of monocytes, as well as the functional changes that occur in infected macrophages.
Research Projects
Mechanisms of HCMV Dissemination and Persistence. We recently documented that monocytes/macrophages are likely the principal cell type responsible for HCMV spread to peripheral organs following primary infection and are a key reservoir for viral persistence, suggesting these cells are the source of the initial spread to host organ tissue and for the long-term viral persistence observed in the host. It is this viral strategy of utilizing monocytes/macrophages for viral dissemination and persistence that links HCMV infection to viral-mediated pathogenesis, such as in the end-organ disease observed in AIDS and transplant patients and in congenitally infected neonates, and in the development of certain solid organ tumors.
Mechanistically, we propose the following model for viral spread. Monocytes are infected in the blood, although not productively at the time of initial infection, and are induced by viral binding to cognate receptors to extravasate into various tissues. There they differentiate into long-lived macrophages, which support replication of the original input virus, allowing for viral persistence in target organs. The ability to drive monocyte extravasation and monocyte-to-macrophage differentiation appears to be an essential function of the virus. To our knowledge, there is no precedent for this strategy in other viruses. But how does HCMV influence monocyte function and force these infected cells to serve as Trojan Horses for hematogenous dissemination? We have data that viral induction of specific signaling pathways in infected monocytes is essential for their activation following infection, suggesting viral manipulation of these pathways serve as a key molecular determinant of viral dissemination. Previously, we identified that the envelope glycoproteins stimulated rapid activation, identifying a viral receptor/ligand interaction as the trigger for the changes in monocytes during infection. The HCMV mediated changes in monocytes following infection are not mimicked by other viruses or known monocyte-activating agents, suggesting that the HCMV receptor/ligand interaction initiates a unique biological programming in infected monocytes.
To understand these viral-mediated changes in monocytes, we are actively investigating the underlying mechanisms responsible for these changes in monocytes. These results will provide insight into a mechanism by which HCMV infection initiates the unique molecular changes in infected monocytes that trigger the biological processes required for viral spread and persistence. Furthermore the decoding of the mechanisms responsible for these changes in infected monocytes will provide molecular clues to the underlying causes of HCMV pathogenesis, as well as identify new potential targets for therapeutic intervention.
HCMV Infection of Endothelial Cells Induces a Pro-Angiogenic Response. Cardiovascular diseases are the primary cause of death in the United States, with atherosclerosis and its complications accounting for a majority of these deaths. HCMV is a primary viral candidate in the etiology of atherosclerosis, as evidence links HCMV infection to the development and severity of atherosclerotic disease. The cells associated with disease pathology (endothelial cells, monocytes, and smooth muscle cells) are primary in vivo targets for the virus. Endothelial cells line blood vessels, separating blood from the vessel wall; they provide a non-thrombogenic layer, make key cytokines and growth factors, and are the first cells to be altered/damaged during disease progression. We now have the initial evidence that direct HCMV infection of endothelial cells induces proliferation, migration, and tubular morphogenesis in infected endothelial cells, all hallmarks of angiogenesis.
Angiogenesis is a complex biological process that results in the formation of new capillary tubes. While angiogenesis is a normal process in the host, its dysregulation, following viral infection or injury to the vessel wall, is associated with plaque development in atherosclerotic patients, as well as in growth of solid organ tumors. Mechanistically, our data shows that specific viral manipulation of host cell pathways serves as the key molecular determinant for the viral-induced angiogenesis. Because a pro-angiogenic response drives neovascularization, our findings identify a possible mechanism for how HCMV infection contributes to vascular disease and possibly oncogenesis.
To decipher how HCMV promotes angiogenesis we are actively investigating the signaling pathways usurped in infected endothelial cells that initiate the distinct molecular changes in infected endothelial cells that drive a pathological process. The identification of the pathways that regulate the viral mediated angiogenesis will provide evidence for why HCMV infection is considered a significant risk factor for the development of vascular disease and certain tumors.
Selected Publications
Klimstra, W. B., E. L. Nangle, M. S. Smith, A. D. Yurochko, and K. D. Ryman. 2003. DC-SIGN and L-SIGN can act as attachment and entry receptors for alphaviruses and distinguish between mosquito cell- and mammalian cell-derived virus. J. Virol. 77:12022-12032.
Smith, M. S., G. L. Bentz, and A. D. Yurochko. 2004. Human cytomegalovirus induces monocyte-to-macrophage differentiation as a strategy to promote viral dissemination and persistence. J. Virol. 78:4444-4453.
DeMeritt, I. B., L. E. Milford, and A. D. Yurochko. 2004. Activation of the NF-kB pathway in HCMV-infected cells is necessary for transactivation of the major immediate-early promoter. J. Virol. 78:4498-4507.
Smith, M.S., G.L. Bentz, P.M. Smith, E.R. Bivins, and A.D. Yurochko. 2004. HCMV activates PI(3)K in monocytes and promotes monocyte motility and transendothelial migration in a PI(3)K-dependent manner. J. Leukoc. Biol.. 76:65-76.
Castillo, J.P., F.M. Frame, H.A. Rogoff, M.T. Pickering, A.D. Yurochko, and T.F. Kowalik. 2005. HCMV IE1
72 activates ataxia telangiectasia mutated kinase and a p53/p21-mediated growth arrest response. J. Virol.
79:11467-11475.
DeMeritt, I.B., J.P. Podduturi, A.M. Tilley, M.T. Nogalski, and A.D. Yurochko. 2006. Prolonged activation of
NF-kB by human cytomegalovirus promotes efficient viral replication and late gene expression. Virology. 346:15
31.