Thomas E. Shenk

Position
James A. Elkins Jr. Professor in the Life Sciences, Emeritus
Role
Professor of Molecular Biology, Emeritus
Bio/Description

Focus

Human cytomegalovirus replication and pathogenesis

Research

Cytomegaloviruses are members of the herpes virus family. Human cytomegalovirus (HCMV) infections are widespread and subclinical in the vast majority of cases, but the virus exhibits increased virulence in the very young and old and in immunocompromised individuals. Congenital infections cause life-long disabilities in a significant number of children. Transplant recipients, cancer patients, and AIDS patients, all of whom can exhibit decreased immune function, suffer a variety of clinical manifestations resulting from cytomegalovirus infection, including mononucleosis and pneumonia. There are also suggestions in the literature that HCMV might serve as a cofactor in certain cancers, atherosclerosis and immune senescence. The HCMV particle carries a viral genome comprised of linear double-stranded DNA that encodes more than 200 proteins, 23 microRNAs and a variety of additional non-coding RNAs. We study molecular mechanisms underlying HCMV replication and pathogenesis, as well as viral latency.

When the virus infects a fibroblast, epithelial cell or endothelial cell, it actively replicates and generates infectious progeny. We have studied the HCMV life cycle by using a mixture of genetic, biochemical, proteomic and metabolomic approaches. One area of special interest to us has been the identification of mechanisms by which the virus blocks defensive responses of the host cell, an area where the HCMV pUL38 protein plays a major role. We constructed a mutant virus unable to express pUL38 and found that it failed to efficiently express all viral genes tested and infected cells died of apoptosis before the viral replication cycle was completed. Using proteomic analysis, we discovered that pUL38 binds to the cellular tuberous sclerosis protein complex (TSC). This is a tumor suppressor complex that interprets stress signals and modulates the activity of mTOR, which in turn controls translation, fatty acid synthesis and many other vital processes in the cell. The pUL38 protein blocks the ability of TSC to respond to upstream signals, allowing the virus to continue to utilize cellular biosynthetic systems in spite of inducing a strong stress response. We further probed the HCMV-host cell interaction by studying how metabolism is altered by infection. This work revealed that HCMV induces glycolysis, nucleotide synthesis, citric acid cycle flux and lipid biosynthesis. Inhibition of the committed step of fatty acid synthesis and elongation, acetyl-CoA carboxylase, blocks HCMV replication, so we performed an siRNA screen and identified a substantial number of enzymes that sponsor fatty acid and lipid biosynthesis and are needed for successful virus replication. This analysis also revealed that each of the seven human sirtuins is an HCMV restriction factor. Sirtuins are NAD+-dependent protein deacetylases, and we have determined that modulation of sirtuin activity can inhibit many different viruses.

When HCMV infects a bone marrow stem cell or a monocyte, it doesn't replicate. Rather, it enters a state of quiescence termed latency. We have developed and validated two cell culture models for latency. Using these models, we have discovered that the virus transiently expresses a large number of viral products after infecting these cells, but after several days the viral genome becomes quiescent.

Most recently we have begun to investigate how cellular long non-coding RNAs influence HCMV, and we have discovered that HSATII RNA is strongly induced by infection and required for the production of an optimal virus yield. We are currently investigating the mechanism by which it impacts the HCMV replication cycle.

Biography

Thomas Shenk, Ph.D., is the James A. Elkins Professor of Life Sciences, Emeritus in the Department of Molecular Biology at Princeton University. He is a virologist, who has investigated gene functions and pathogenesis of adenovirus, a DNA tumor virus, and, more recently, human cytomegalovirus, a member of the herpes family of viruses. Cytomegalovirus is the leading known infectious cause of birth defects, it is responsible for significant morbidity in people who become immunosuppressed, and there is suggestive evidence that it contributes to certain cancers and immune senescence. His laboratory’s current areas of focus include the use of genetic and proteomic approaches for the dissection of cytomegalovirus gene functions and the cellular response to infection, as well as the development and analysis of models for study of viral latency. Professor Shenk is a fellow of the American Academy of Microbiology and the American Academy of Arts and Sciences; and he is a member of the U.S. National Academy of Sciences and the U.S. Institute of Medicine.  He is a past president of the American Society for Virology and the American Society for Microbiology, and he served on the board of directors of Merck & Company for 11 years. He currently serves as a member of the boards of directors of the Fox Chase Cancer Center, The Hepatitis B Foundation and Origen Therapeutics.

Honors & Awards

2013

  • Intellectual Property Accelerator Award, Princeton University

2012

  • Arthur Kornberg and Paul Berg Lifetime Achievement Award in Biomedical Sciences, Stanford Medical Center

Selected Publications