About

Thomas E. Shenk 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 the pathogenesis of adenovirus, a DNA tumor virus, and human cytomegalovirus (HCMV), a member of the herpes family of viruses. His research focuses on understanding the molecular mechanisms underlying HCMV replication and pathogenesis, as well as viral latency. His laboratory employs genetic, biochemical, proteomic, and metabolomic approaches to study the HCMV life cycle, including how the virus blocks host cell defenses and alters cellular metabolism during infection. Key areas of his work include identifying viral proteins such as pUL38 that interact with host cellular complexes, studying how HCMV induces metabolic pathways like glycolysis and lipid biosynthesis, and developing models for viral latency. His research also explores the role of cellular long non-coding RNAs, such as HSATII RNA, in viral replication. Dr. Shenk is a fellow of the American Academy of Microbiology and the American Academy of Arts and Sciences, and a member of the U.S. National Academy of Sciences and the U.S. Institute of Medicine. He has served as past president of the American Society for Virology and the American Society for Microbiology, and has been a member of the board of directors of Merck & Co. He currently serves on the boards of the Fox Chase Cancer Center, The Hepatitis B Foundation, and Origen Therapeutics.

Research topics

• Virology
• Immunology
• Medicine
• Political Science
• Pathology
• Biology

Selected publications

• The Story behind the Science: On the discovery of respiratory syncytial virus

  mBio · 2025-01-21 · 4 citations

  reviewOpen access

  Respiratory syncytial virus (RSV) was discovered in 1956 by the laboratory of Robert Chanock after its isolation from children with upper respiratory infections. Here, we review the events leading to its discovery including its prior isolation as chimpanzee coryza virus and its subsequent association with human disease.

  PublisherDOI

• Structural basis for sirtuin 2 activity and modulation: Current state and opportunities

  Journal of Biological Chemistry · 2025-05-22 · 9 citations

  reviewOpen access

  as a cofactor. SIRT2-mediated posttranslational modifications on a plethora of protein targets position the enzyme to exert a wide-ranging regulatory role in many physiological and pathological processes. More than 39 SIRT2 crystal structures in complex with substrates, products, mimetics of substrates and products, and modulators have been reported. The Rossmann fold of the catalytic core presents inducible acyl and cofactor-binding cavities that accommodate acyl chains of diverse lengths. These structures have provided information for the design of mechanism- and substrate-based inhibitors. Indeed, a specific SIRT2 selectivity pocket has been described and can be targeted by different chemotypes. Despite the determination of many crystal structures, numerous open questions remain, especially relating to the development of small molecule modulators, full or partial activation or inhibition, and relating these effects to different therapeutic applications. Additional questions include understanding the role of the disordered termini and the role of potential quaternary states (monomer, dimer, and trimer). Deeper insight into these issues may facilitate the development of SIRT2 selective modulators that can be tailored to different pathological scenarios, such as viral infections and cancers, in which either activation or inhibition of SIRT2 may be of therapeutic benefit. This review covers the following topics: (1) primary to quaternary and catalytic structural biology; (2) structural insights into molecular modulation of SIRT2 (inhibition and selectivity by mechanism-based inhibitors, substrate-mimicking inhibitors, C pocket-binding inhibitors, and selectivity pocket binding inhibitors, including insights to activation); and (3) the impact of structural variations (mutations, posttranslational modifications, polymorphs, protein interactions). Despite considerable progress, key knowledge gaps remain regarding the design of optimized SIRT2 modulators. Addressing these uncertainties, particularly within the realms of full/partial activation/inhibition, off-target effects, and tailoring modulators to specific pathologies, will require further investigation into the roles of the SIRT2-disordered termini, quaternary states, and posttranslational modifications. Ultimately, unraveling these intricacies holds the key to unlocking the therapeutic potential of SIRT2 modulation.

  PublisherOA PDFDOI

• Drugs Targeting Sirtuin 2 Exhibit Broad-Spectrum Anti-Infective Activity

  Pharmaceuticals · 2024-09-29 · 2 citations

  reviewOpen access1st authorCorresponding

  Direct-acting anti-infective drugs target pathogen-coded gene products and are a highly successful therapeutic paradigm. However, they generally target a single pathogen or family of pathogens, and the targeted organisms can readily evolve resistance. Host-targeted agents can overcome these limitations. One family of host-targeted, anti-infective agents modulate human sirtuin 2 (SIRT2) enzyme activity. SIRT2 is one of seven human sirtuins, a family of NAD+-dependent protein deacylases. It is the only sirtuin that is found predominantly in the cytoplasm. Multiple, structurally distinct SIRT2-targeted, small molecules have been shown to inhibit the replication of both RNA and DNA viruses, as well as intracellular bacterial pathogens, in cell culture and in animal models of disease. Biochemical and X-ray structural studies indicate that most, and probably all, of these compounds act as allosteric modulators. These compounds appear to impact the replication cycles of intracellular pathogens at multiple levels to antagonize their replication and spread. Here, we review SIRT2 modulators reported to exhibit anti-infective activity, exploring their pharmacological action as anti-infectives and identifying questions in need of additional study as this family of anti-infective agents advances to the clinic.

  PublisherOA PDFDOI

• An allosteric inhibitor of sirtuin 2 blocks hepatitis B virus covalently closed circular DNA establishment and its transcriptional activity

  Antiviral Research · 2024-04-18 · 8 citations

  articleOpen accessSenior author
  PublisherOA PDFDOI

• Virology under the Microscope—a Call for Rational Discourse

  mSphere · 2023 · 9 citations

  • Political Science
  • Virology
  • Medicine

  Viruses have brought humanity many challenges: respiratory infection, cancer, neurological impairment and immunosuppression to name a few. Virology research over the last 60+ years has responded to reduce this disease burden with vaccines and antivirals. Despite this long history, the COVID-19 pandemic has brought unprecedented attention to the field of virology. Some of this attention is focused on concern about the safe conduct of research with human pathogens. A small but vocal group of individuals has seized upon these concerns - conflating legitimate questions about safely conducting virus-related research with uncertainties over the origins of SARS-CoV-2. The result has fueled public confusion and, in many instances, ill-informed condemnation of virology. With this article, we seek to promote a return to rational discourse. We explain the use of gain-of-function approaches in science, discuss the possible origins of SARS-CoV-2 and outline current regulatory structures that provide oversight for virological research in the United States. By offering our expertise, we - a broad group of working virologists - seek to aid policy makers in navigating these controversial issues. Balanced, evidence-based discourse is essential to addressing public concern while maintaining and expanding much-needed research in virology.

  PublisherDOI

• An allosteric inhibitor of sirtuin 2 deacetylase activity exhibits broad-spectrum antiviral activity

  Journal of Clinical Investigation · 2023-06-14 · 26 citations

  articleOpen access

  Most drugs used to treat viral disease target a virus-coded product. They inhibit a single virus or virus family, and the pathogen can readily evolve resistance. Host-targeted antivirals can overcome these limitations. The broad-spectrum activity achieved by host targeting can be especially useful in combating emerging viruses and for treatment of diseases caused by multiple viral pathogens, such as opportunistic agents in immunosuppressed patients. We have developed a family of compounds that modulate sirtuin 2, an NAD+-dependent deacylase, and now report the properties of a member of that family, FLS-359. Biochemical and x-ray structural studies show that the drug binds to sirtuin 2 and allosterically inhibits its deacetylase activity. FLS-359 inhibits the growth of RNA and DNA viruses, including members of the coronavirus, orthomyxovirus, flavivirus, hepadnavirus, and herpesvirus families. FLS-359 acts at multiple levels to antagonize cytomegalovirus replication in fibroblasts, causing modest reductions in viral RNAs and DNA, together with a much greater reduction in infectious progeny, and it exhibits antiviral activity in humanized mouse models of infection. Our results highlight the potential of sirtuin 2 inhibitors as broad-spectrum antivirals and set the stage for further understanding of how host epigenetic mechanisms impact the growth and spread of viral pathogens.

  PublisherOA PDFDOI

• Paul Berg: Recombinant DNA trailblazer

  Proceedings of the National Academy of Sciences · 2023-11-13 · 2 citations

  articleOpen accessSenior authorCorresponding

  Understanding the biological basis of social anxiety disorder (SAD), one of the most disabling of the anxiety disorders, will allow for novel treatment strategies to be developed. Here, we show that gut microbiota may be such a target. Mice ...Social anxiety disorder (SAD) is a crippling psychiatric disorder characterized by intense fear or anxiety in social situations and their avoidance. However, the underlying biology of SAD is unclear and better treatments are needed. Recently, the gut ...

  PublisherOA PDFDOI

• Virology under the Microscope—a Call for Rational Discourse

  Journal of Virology · 2023 · 20 citations

  • Biology
  • Virology
  • Immunology

  Viruses have brought humanity many challenges: respiratory infection, cancer, neurological impairment and immunosuppression to name a few. Virology research over the last 60+ years has responded to reduce this disease burden with vaccines and antivirals. Despite this long history, the COVID-19 pandemic has brought unprecedented attention to the field of virology. Some of this attention is focused on concern about the safe conduct of research with human pathogens. A small but vocal group of individuals has seized upon these concerns - conflating legitimate questions about safely conducting virus-related research with uncertainties over the origins of SARS-CoV-2. The result has fueled public confusion and, in many instances, ill-informed condemnation of virology. With this article, we seek to promote a return to rational discourse. We explain the use of gain-of-function approaches in science, discuss the possible origins of SARS-CoV-2 and outline current regulatory structures that provide oversight for virological research in the United States. By offering our expertise, we - a broad group of working virologists - seek to aid policy makers in navigating these controversial issues. Balanced, evidence-based discourse is essential to addressing public concern while maintaining and expanding much-needed research in virology.

  PublisherDOI

• The aryl hydrocarbon receptor facilitates the human cytomegalovirus-mediated G1/S block to cell cycle progression

  Proceedings of the National Academy of Sciences · 2021-03-15 · 16 citations

  articleOpen accessSenior authorCorresponding

  The tryptophan metabolite, kynurenine, is known to be produced at elevated levels within human cytomegalovirus (HCMV)-infected fibroblasts. Kynurenine is an endogenous aryl hydrocarbon receptor (AhR) ligand. Here we show that the AhR is activated following HCMV infection, and pharmacological inhibition of AhR or knockdown of AhR RNA reduced the accumulation of viral RNAs and infectious progeny. RNA-seq analysis of infected cells following AhR knockdown showed that the receptor alters the levels of numerous RNAs, including RNAs related to cell cycle progression. AhR knockdown alleviated the G1/S cell cycle block that is normally instituted in HCMV-infected fibroblasts, consistent with its known ability to regulate cell cycle progression and cell proliferation. In sum, AhR is activated by kynurenine and perhaps other ligands produced during HCMV infection, it profoundly alters the infected-cell transcriptome, and one outcome of its activity is a block to cell cycle progression, providing mechanistic insight to a long-known element of the virus-host cell interaction.

  PublisherOA PDFDOI

• HSATII RNA is induced <i>via</i> a non-canonical ATM-regulated DNA-damage response pathway and facilitates tumor cell proliferation and movement

  bioRxiv (Cold Spring Harbor Laboratory) · 2020-05-25

  preprintOpen accessSenior author

  ABSTRACT Pericentromeric human satellite II (HSATII) repeats are normally silent, but can be actively transcribed in tumor cells, where increased HSATII copy number is associated with a poor prognosis in colon cancer, and in human cytomegalovirus (HCMV)-infected cells, where the RNA facilitates viral replication. Here, we report that HCMV infection or treatment of ARPE-19 diploid epithelial cells with the DNA-damaging agents, etoposide and zeocin, induced HSATII RNA expression, and a kinase-independent function of ATM was required for the induction. Additionally, various breast cancer cell lines growing in adherent, 2-dimensional cell culture expressed HSATII RNA at different levels, and levels were markedly increased when cells were either infected with HCMV or treated with zeocin. High levels of HSATII RNA expression correlated with enhanced migration of breast cancer cells, and knockdown of HSATII RNA reduced cell migration and the rate of cell proliferation. Our investigation links high expression of HSATII RNA to the DNA damage response, centered on a non-canonical function of ATM, and demonstrates a role for the satellite RNA in tumor cell proliferation and movement. SIGNIFICANCE HSATII RNA is associated with cancer progression, immunostimulation and, as we recently reported, it plays an important role in herpesvirus infections. However, the understanding of cellular processes responsible for the expression of HSATII RNA has been limited. Our current investigation identified a non-canonical, ATM kinase-independent DNA-damage response pathway as a common cellular mechanism regulating HSATII RNA induction in virus-infected cells or cells treated with DNA-damaging agents. Additionally, our study provides a link between expression of HSATII RNA and the cellular growth and migration phenotypes of cancer cells, establishing a new paradigm to study the biological consequences of HSATII RNA expression, i.e., treatment of normal diploid and tumor cells with DNA-damaging agents.

  PublisherOA PDFDOI

Recent grants

• NIH Grant R56AI112951

  NIH · $399k · 2014

• NIH Grant R01CA085786

  NIH · $3.7M · 2011

• NIH Grant R01AI087672

  NIH · $1.8M · 2016

• An experimental system designed to identify human cytomegalovirus-induced alterations in tumor cells and test their dependence on continued viral gene expression

  NIH · $446k · 2018–2021

• NIH Grant R01CA082396

  NIH · $5.3M · 2015

Frequent coauthors

• Felicia Goodrum

  University of Arizona

  34 shared

• Miklós Tóth

  Cornell University

  31 shared

• Jay A. Nelson

  Ambrx (United States)

  29 shared

• Kevin P. High

  Cincinnati Children's Hospital Medical Center

  27 shared

• David A. Ornelles

  Wake Forest University

  27 shared

• Eain A. Murphy

  SUNY Upstate Medical University

  26 shared

• Craig T. Jordan

  26 shared

• Anny Usheva

  Bryn Mawr College

  26 shared

Labs

• Shenk LabPI

Awards & honors

• 2013 Intellectual Property Accelerator Award, Princeton Univ…
• 2012 Arthur Kornberg and Paul Berg Lifetime Achievement Awar…