Publications by authors named "Thomas Shenk"

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.

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296 million people worldwide are predisposed to developing severe end-stage liver diseases due to chronic hepatitis B virus (HBV) infection. HBV forms covalently closed circular DNA (cccDNA) molecules that persist as episomal DNA in the nucleus of infected hepatocytes and drive viral replication. Occasionally, the HBV genome becomes integrated into host chromosomal DNA, a process that is believed to significantly contribute to circulating HBsAg levels and HCC development.

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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.

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Article Synopsis
  • Viruses pose significant health challenges, leading to issues like respiratory infections, cancer, and neurological impairments, but virology research has developed vaccines and antivirals to mitigate these problems.
  • The COVID-19 pandemic has heightened public scrutiny of virology, especially regarding the safe conduct of research with human pathogens, leading to confusion and misinterpretation about the origins of SARS-CoV-2.
  • This article aims to clarify misconceptions by explaining gain-of-function research, the origins of SARS-CoV-2, and the regulatory frameworks in place, fostering informed discussions and emphasizing the need for balanced, evidence-based dialogue in virology.
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Article Synopsis
  • Viruses have historically caused serious health issues, including respiratory infections and cancer, leading to significant virology research that resulted in vaccines and antiviral treatments.
  • The COVID-19 pandemic highlighted the necessity for careful research on human pathogens, creating both concerns and confusion about the safety of virology work and the origins of SARS-CoV-2.
  • The article aims to clarify misunderstandings by explaining gain-of-function research, exploring the origins of SARS-CoV-2, and discussing regulatory oversight, while advocating for rational and evidence-based discussions to guide policy decisions in virology.
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Article Synopsis
  • Viruses pose significant health challenges, leading to various issues such as respiratory infections and cancer, prompting virology research to develop vaccines and antiviral treatments over the past 60+ years.
  • The COVID-19 pandemic has intensified focus on virology, bringing up safety concerns about research involving human pathogens and creating public confusion between safe research practices and the origins of SARS-CoV-2.
  • The article aims to clarify these issues by discussing gain-of-function research, the origins of SARS-CoV-2, and current regulatory frameworks, advocating for informed, balanced conversations to support necessary virology research.
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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.

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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 fibroblasts, where the RNA facilitates viral replication. Here, we report that HCMV infection or treatment of ARPE-19 diploid epithelial cells with DNA-damaging agents, etoposide or zeocin, induces HSATII RNA expression, and a kinase-independent function of ATM is required for the induction. Additionally, various breast cancer cell lines growing in adherent, two-dimensional cell culture express HSATII RNA at different levels, and levels are markedly increased when cells are infected with HCMV or treated with zeocin.

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Human cytomegalovirus (HCMV) manipulates many aspects of host cell biology to create an intracellular milieu optimally supportive of its replication and spread. Our study reveals that levels of several components of the purinergic signaling system, including the P2Y2 and P2X5 receptors, are elevated in HCMV-infected fibroblasts. Knockdown and drug treatment experiments demonstrated that P2Y2 enhances the yield of virus, whereas P2X5 reduces HCMV production.

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Tandem satellite repeats account for 3% of the human genome. One of them, Human Satellite II (HSATII), is highly expressed in several epithelial cancers and cancer cell lines. Here we report an acute induction of HSATII RNA in human cells infected with two herpes viruses.

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Human CMV (HCMV) exhibits a broad cell tropism that depends on two virion glycoprotein complexes: a trimeric complex (gH/gL/gO) that facilitates viral infection primarily in fibroblasts and a pentameric complex (gH/gL/pUL128-pUL130-pUL131A) that mediates infection in epithelial and endothelial cells. We performed genome-wide CRISPR screens in which the PDGF receptor-α (PDGFRα) was identified as the most significant cellular gene product essential for infection by HCMV virions containing only trimeric complex (trimer-only virus). Trimer-only virus did not enter PDGFRα knockout fibroblasts.

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Human cytomegalovirus (HCMV) is the prototypical human β-herpes virus. Here we perform a systems analysis of the HCMV host-cell transcriptome, using gene set enrichment analysis (GSEA) as an engine to globally map the host-pathogen interaction across two cell types. Our analysis identified several previously unknown signatures of infection, such as induction of potassium channels and amino acid transporters, derepression of genes marked with histone H3 lysine 27 trimethylation (H3K27me3), and inhibition of genes related to epithelial-to-mesenchymal transition (EMT).

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Many scientists attempt to publish their work in a journal with the highest possible journal impact factor (IF). Despite widespread condemnation of the use of journal IFs to assess the significance of published work, these numbers continue to be widely misused in publication, hiring, funding, and promotion decisions (1, 2).

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Many scientists attempt to publish their work in a journal with the highest possible journal impact factor (IF). Despite widespread condemnation of the use of journal IFs to assess the significance of published work, these numbers continue to be widely misused in publication, hiring, funding, and promotion decisions (1, 2).

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