Michael Nevels

Michael Nevels
University of St Andrews · BioMedical Sciences Research Complex

Dr. rer. nat.

About

85
Publications
5,417
Reads
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2,152
Citations
Introduction
I've been doing virology research and teaching in Germany, the USA and the UK. My favorite virus is the human cytomegalovirus (hCMV). hCMV is an important, but somewhat neglected pathogen and the most complex known human virus. My lab members and I are committed to understanding this virus and to helping others develop novel prevention, detection and treatment strategies for hCMV infection. We also provide training in basic lab skills and molecular virology to undergraduate, PhD and MD students.
Additional affiliations
April 2015 - present
Institute for Medical Microbiology and Hygiene
Position
  • Professor (Associate)
March 2015 - July 2016
University of St Andrews
Position
  • Reader (Associate Professor) in Virology
March 2015 - July 2016
University of St Andrews
Position
  • Reader (Associate Professor) in Virology

Publications

Publications (85)
Article
This communication summarizes the presentations given at the 1st international conference of the World Society for Virology (WSV) held virtually during 16–18 June 2021, under the theme of tackling global viral epidemics. The purpose of this biennial meeting is to foster international collaborations and address important viral epidemics in different...
Article
Full-text available
The genomes of DNA tumor viruses regain nuclear localization after nuclear envelope breakdown during mitosis through the action of a viral protein with a chromatin-tethering domain (CTD). Here, we report that the human cytomegalovirus (HCMV) genome is maintained during mitosis by the CTD of the viral IE19 protein. Deletion of the IE19 CTD or disrup...
Article
Full-text available
Tethering of viral genomes to host chromosomes has been recognized in a variety of DNA and RNA viruses. It can occur during both the productive cycle and latent infection and may impact viral genomes in manifold ways including their protection, localization, transcription, replication, integration, and segregation. Tethering is typically accomplish...
Article
Promyelocytic leukaemia (PML) bodies are nuclear organelles implicated in post-translational modification by small ubiquitin-like modifier (SUMO) proteins and in the antiviral host cell response to infection. The 72-kDa immediate-early protein 1 (IE1) is considered the principal antagonist of PML bodies encoded by the human cytomegalovirus, one of...
Article
Full-text available
Promyelocytic leukemia (PML) bodies are nuclear organelles implicated in intrinsic and innate antiviral defense. The eponymous PML proteins, central to the self-organization of PML bodies, and other restriction factors found in these organelles are common targets of viral antagonism. The 72-kDa immediate-early protein 1 (IE1) is the principal antag...
Article
Full-text available
PML nuclear bodies (PML-NBs) are implicated in general antiviral defense based on recruiting host restriction factors; however, it is not understood so far why viruses would establish viral replication centers (RCs) juxtaposed to such “antiviral” compartments. To understand this enigma, we investigate the cross talk between PML-NB components and vi...
Article
Full-text available
The human cytomegalovirus (HCMV), one of eight human herpesviruses, establishes lifelong latent infections in most people worldwide. Primary or reactivated HCMV infections cause severe disease in immunosuppressed patients and congenital defects in children. There is no vaccine for HCMV, and the currently approved antivirals come with major limitati...
Article
Full-text available
DNA damage can be sensed as a danger-associated molecular pattern by the innate immune system. Here we find that keratinocytes and other human cells mount an innate immune response within hours of etoposide-induced DNA damage, which involves the DNA sensing adaptor STING but is independent of the cytosolic DNA receptor cGAS. This non-canonical acti...
Article
The relationship between human cytomegalovirus (HCMV) and tumours has been extensively investigated, mainly in glioblastoma multiforme (GBM), a malignant tumour of the central nervous system with low overall survival rates. Several reports have demonstrated the presence of HCMV in GBM, although typically restricted to a low number of cells, and stu...
Article
The mechanisms underlying neurodevelopmental damage caused by virus infections remain poorly defined. Congenital human cytomegalovirus (HCMV) infection is the leading cause of fetal brain development disorders. Previous work has linked HCMV to perturbations of neural cell fate, including premature differentiation of neural progenitor cells (NPCs)....
Preprint
Full-text available
The mechanisms underlying neurodevelopmental damage caused by virus infections remain poorly defined. Congenital human cytomegalovirus (HCMV) infection is the leading cause of fetal brain development disorders. Previous work has linked HCMV to perturbations of neural cell fate, including premature differentiation of neural progenitor cells (NPCs)....
Article
Full-text available
Viral interferon (IFN) antagonists are a diverse class of viral proteins that counteract the host IFN response, which is important for controlling viral infections. Viral IFN antagonists are often multifunctional proteins that perform vital roles in virus replication beyond IFN antagonism. The critical importance of viral IFN antagonists is highlig...
Article
Full-text available
Congenital human cytomegalovirus (HCMV) infection is the leading cause of neurological disabilities in children worldwide, but the mechanisms underlying these disorders are far from well-defined. HCMV infection has been shown to dysregulate the Notch signaling pathway in human neural progenitor cells (NPCs). As an important downstream effector of N...
Data
IE1 but not Δ451–475 shortens the half-life of exogenous Hes1. (A) 293T cells were transfected with 1μg pCDH-Hes1 and 5μg pEYFP (vector), pEYFP-IE1 (IE1) or pEYFP-IE1(Δ451–475) (Δ451–475). At 24hpt, cells were treated with 0.1mg/ml CHX and harvested at the indicated times post CHX treatment. The cell lysates were subjected to immunoblotting to exam...
Data
Prokaryotically expressed and purified proteins. His-Hes1, His-Δ451–475 and His-IE1 (A) or His-Sp100A and His-IE1 (B) were prokaryotically expressed, and purified as described in Materials and Methods. The indicated proteins in the according cell lysates, purified and/or concentrated protein samples were subjected to SDS-PAGE and subsequently stain...
Data
DNA and RNA are removed from the cell lysate by DNase/RNase treatment. Lysates of 293T cells were treated with 10,000 units DNase and 10μg RNase for 1h. DNA and RNA in non-treated and treated samples were visualized by ethidium bromide staining. (TIF)
Data
Interaction between Hes1 and IE1 or Δ421–475. (A) IE1/Hes1 interaction at different ratios. 293T cells were transfected with pCDH-Hes1 (Hes1) together with pEYFP-IE1 (IE1) or pEYFP (vector) at the indicated amounts. Cells were harvested at 48hpt and cell lysates were subjected to IE1-directed IP followed by IB against IE1 and Hes1. The proteins in...
Data
Overexpressed Hes1 downregulates IE1/2 expression in HELs. Following transduction with lentiviruses expressing Hes1 (Hes1) or control (Ctl), HELs were infected with HCMV (MOI = 0.1) and examined for the protein levels of Hes1, IE1 and IE2 at the indicated time points by IB. β-actin served as a loading control. ND, not detectable. (TIF)
Data
Downregulation of NICD1 and Jag1 proteins during HCMV infection in NPCs. Following mock (M)- or HCMV (V)-infection at an MOI of 3, NPCs were collected at the indicated times, and subjected to IB to examine IE1/2, NICD1, Jag1 and Hes1 proteins with β-actin as loading control. The values listed below the blots indicate the relative protein levels com...
Article
Full-text available
Importance: Kaposi's sarcoma-associated herpesvirus (KSHV) is the causative agent of fatal malignancies of immunocompromised individuals, including Kaposi's sarcoma (KS). Herpesviruses are able to establish a latent infection, where they escape immune detection by restricting viral gene expression. Importantly however, reactivation of productive v...
Article
Full-text available
The human cytomegalovirus (hCMV) major immediate-early 1 protein (IE1) is best known for activating transcription to facilitate viral replication. Here we present transcriptome data indicating that IE1 is as significant a repressor as it is an activator of host gene expression. Human cells induced to express IE1 exhibit global repression of IL6- an...
Data
Residues 405–491 within the IE1 C-terminal domain are sufficient for STAT3 binding. 293T cells were transfected with plasmids encoding mCherry-HA, mCherry-HA-IE1 (wild-type), or mCherry-HA-NLS-IE1dl1-404 fusion proteins. At 48 h post transfection, whole cell extracts were prepared and subjected to immunoprecipitations with anti-HA magnetic beads. S...
Data
Human genes significantly up- or down-regulated by IE1 in the TetR-IE1 cell model. The listed probe sets are linked to average changes of ≥1.5-fold (up-regulated probe sets) or ≤-1.5-fold (down-regulated probe sets) at a significance level of 0.001 (confidence interval, CI = 99.9%) in GeneChip analyses comparing dox-treated TetR-IE1 (TetR-IE1+) to...
Data
The majority of human genes down-regulated by IE1 are STAT3 target genes. MRC-5 cells transduced to express inducible shRNAs targeting firefly luciferase (shLUC) or human STAT3 (shSTAT3_1 and shSTAT3_2) were treated with dox for 72 h. Relative mRNA levels were determined by RT-qPCR with primers specific for the indicated cellular genes. Results wer...
Data
Nuclear accumulation of STAT3 in hCMV-infected cells. (A) MRC-5 cells were mock-infected or infected with TBwt, TBIE1dl410-420 or TBrvIE1dl410-420 at high input multiplicity (5 PFU/cell). At 24 h post infection, subcellular localization of endogenous STAT3 was analyzed by indirect immunofluorescence microscopy. Samples were simultaneously reacted w...
Data
Down-regulation of genes responsive to STAT3, IL6 or/and OSM precedes up-regulation of genes responsive to STAT1 or/and IFNγ by IE1. Maximum average expression changes in genes ≥1.5-fold down- or up-regulated by IE1 (based on S1 Data) and regulated by STAT3, IL6 or/and OSM or STAT1 or/and IFNγ, respectively (based on Ingenuity Pathway Analysis), ar...
Data
IE1 rewires IL6 signaling to STAT1 activation also late in hCMV infection. (A) MRC-5 cells were mock-infected or infected with TBwt, TBIE1dl410-420 or TBrvIE1dl410-420 at high input multiplicity (5 PFU/cell). At 6 h post infection, cultures were treated with solvent or IL6 plus IL6R (IL6/Rα). At 72 h post infection, whole cell protein extracts were...
Data
Knock-down of IFNGR1 only modestly affects IE1-mediated induction of IFNγ-stimulated genes. TetR (w/o) or TetR-IE1 (IE1) cells were transfected with a control siRNA or two different siRNAs specific for IFNGR1. From 48 h post siRNA transfection, cells were treated with dox for 72 h. During the last 24 h of dox treatment, cells were treated with IFNγ...
Data
Characterization of recombinant TB40/E BACs. Restriction fragment length analysis of pTB- (A) or pgTB-derived (C) wt, IE1dl410-420 and rvIE1dl410-420 BACs (two independent clones each) after digestion of 1.2 μg DNA with EcoRI and separation in a 0.7% agarose-Tris-acetate-EDTA gel stained with ethidium bromide. 10 ng of pTB- (B) or pgTB-derived (D)...
Data
STAT3 knock-down inhibits replication of gTBwt and gTBIE1dl410-420. (A) MRC-5 cells transduced to express inducible shRNAs targeting firefly luciferase (shLUC) or human STAT3 (shSTAT3) were treated with dox for 72 h and then infected with gTBwt or gTBIE1dl410-420 at low input multiplicity (0.01 PFU/cell). Every 48 h, half of the culture media was r...
Article
The morphogenesis of human cytomegalovirus (HCMV) particles is incompletely understood. Analysis of the protein composition of HCMV virions and subviral dense bodies (DBs) by mass spectrometry provides valuable information to increase our knowledge about viral morphogenesis. Here we addressed the viral proteome of virions and DBs from two fibroblas...
Article
The last 50 years of molecular biological investigations into human adenoviruses (Ads) have contributed enormously to our understanding of the basic principles of normal and malignant cell growth. Much of this knowledge stems from analyses of the Ad productive infection cycle in permissive host cells. Also, initial observations concerning the trans...
Article
Full-text available
The 72-kDa immediate-early 1 (IE1) protein encoded by human cytomegalovirus (hCMV) is a nuclear-localized promiscuous regulator of viral and cellular transcription. IE1 has long been known to associate with host mitotic chromatin, yet the mechanisms underlying this interaction have not been specified. In this study, we identify the cellular chromos...
Article
In the canonical STAT3 signaling pathway, binding of agonist to receptors activates Janus kinases that phosphorylate cytoplasmic STAT3 at tyrosine 705 (Y705). Phosphorylated STAT3 dimers accumulate in the nucleus and drive the expression of genes involved in inflammation, angiogenesis, invasion, and proliferation. Here, we demonstrate that human cy...
Article
Human CMV (hCMV) establishes lifelong infections in most of us, causing developmental defects in human embryos and life-threatening disease in immunocompromised individuals. During productive infection, the viral >230,000-bp dsDNA genome is expressed widely and in a temporal cascade. The hCMV genome does not carry histones when encapsidated but has...
Article
Like their cellular host counterparts, many invading viral pathogens must contend with, modulate, and utilize the host cell's chromatin machinery to promote efficient lytic infection or control persistent-latent states. While not intended to be comprehensive, this review represents a compilation of conceptual snapshots of the dynamic interplay of v...
Article
Full-text available
In the nuclei of permissive cells, human cytomegalovirus genomes form nucleosomal structures initially resembling heterochromatin but gradually switching to a euchromatin-like state. This switch is characterized by a decrease in histone H3 K9 methylation and a marked increase in H3 tail acetylation and H3 K4 methylation across the viral genome. We...
Article
Herpesvirus infections of humans can cause a broad variety of symptoms ranging from mild afflictions to life-threatening disease. During infection, the large double-stranded DNA genomes of all herpesviruses are transcribed, replicated and encapsidated in the host cell nucleus, where DNA is typically structured and manoeuvred through nucleosomes. Nu...
Data
Enrichment of GO “cellular component” (GO:0005575) terms (p<10) in IE1-activated genes. (DOC)
Data
STAT2 knock-down is functionally effective and can down-regulate a bona fide STAT2-responsive gene. MRC-5 cells were transfected with control siRNA #149 or STAT2-specific siRNA #152. Four days post transfection cells were treated with IFN-α (10 ng/ml) for 24 h or were left untreated (w/o). Relative mRNA expression levels were determined by qRT-PCR...
Data
Oligonucleotides used in this study. (DOC)
Data
Time course qRT-PCR analysis of IFN-β and IFN-γ expression. TetR and TetR-IE1 cells were treated with doxycycline for 3 to 96 h or were left untreated (0 h). Relative mRNA expression levels were determined from 5 µl of undiluted cDNA by qRT-PCR with primers specific for the IFNB and IFNG genes. Results were normalized to TUBB, and means of two biol...
Data
qRT-PCR analysis of IFN responsiveness of IE1-induced genes. (DOC)
Data
Results of GeneChip analysis for IFN genes. (DOC)
Data
qRT-PCR analysis of IFN-β and IFN-γ expression. (DOC)
Data
Enrichment of GO “biological process” (GO:0008150) terms (p<0.2) in IE1-activated genes. (DOC)
Data
Enrichment of GO “molecular function” (GO:0003674) terms (p<0.2) in IE1-activated genes. (DOC)
Data
STAT1 binding sites in the promoter regions of IE1-activated human genes. (DOC)
Article
Full-text available
Human cytomegalovirus (hCMV) is a highly prevalent pathogen that, upon primary infection, establishes life-long persistence in all infected individuals. Acute hCMV infections cause a variety of diseases in humans with developmental or acquired immune deficits. In addition, persistent hCMV infection may contribute to various chronic disease conditio...
Article
Human cytomegalovirus (HCMV) is a major pathogen in immunocompromised individuals. Here, non-toxic concentrations of the anti-cancer kinase inhibitor sorafenib were shown to inhibit replication of different HCMV strains (including a ganciclovir-resistant strain) in different cell types. In contrast to established anti-HCMV drugs, sorafenib inhibite...
Article
The double-stranded DNA genomes of herpesviruses exist in at least three alternative global chromatin states characterised by distinct nucleosome content. When encapsidated in virus particles, the viral DNA is devoid of any nucleosomes. In contrast, within latently infected nuclei herpesvirus genomes are believed to form regular nucleosomal structu...
Article
Full-text available
The major immediate-early (IE) gene of human cytomegalovirus (CMV) is believed to have a decisive role in acute infection and its activity is an important indicator of viral reactivation from latency. Although a variety of gene products are expressed from this region, the 72-kDa IE1 and the 86-kDa IE2 nuclear phosphoproteins are the most abundant a...
Article
Full-text available
Our previous work has shown that efficient evasion from type I interferon responses by human cytomegalovirus (hCMV) requires expression of the 72-kDa immediate-early 1 (IE1) protein. It has been suggested that IE1 inhibits interferon signaling through intranuclear sequestration of the signal transducer and activator of transcription 2 (STAT2) prote...
Article
Full-text available
The genomes of herpesviruses, including human cytomegalovirus (CMV), are double-stranded DNA molecules maintained as episomes during infection. The viral DNA lacks histones when encapsidated in the virion. However, it has been found histone associated inside infected cells, implying unidentified chromatin assembly mechanisms. Our results indicate t...
Article
The last 50 yr of molecular biological investigations into human adenoviruses (Ads) have contributed enormously to our understanding of the basic principles of normal and malignant cell growth. Much of this knowledge stems from analyses of the Ad productive infection cycle in permissive host cells. Also, initial observations concerning the transfor...
Article
Full-text available
Type I IFNs are crucial components of the innate immune response to viral attack. They are rapidly synthesized and secreted after infection with human cytomegalovirus (CMV) and trigger a signal transduction pathway that involves successive activation and nuclear translocation of signal transducer and activator of transcription 1 (STAT1) and STAT2....
Article
Full-text available
The human cytomegalovirus 72-kDa immediate-early (IE)1 and 86-kDa IE2 proteins are expressed at the start of infection, and they are believed to exert much of their function through promiscuous transcriptional activation of viral and cellular gene expression. Here, we show that the impaired growth of an IE1-deficient mutant virus in human fibroblas...
Article
Full-text available
The 72-kDa immediate-early 1 protein (IE1-72kDa) of human cytomegalovirus has been previously shown to be posttranslationally modified by covalent conjugation to the ubiquitin-related protein SUMO-1. Using an infectious bacterial artificial chromosome clone of human cytomegalovirus, we constructed a mutant virus (BADpmIE1-K450R) that is deficient f...
Article
Full-text available
Viruses have evolved various strategies to prevent premature apoptosis of infected host cells. Some of the viral genes mediating antiapoptotic functions have been identified by their homology to cellular genes, but others are structurally unrelated to genes of known function. In this study, we used a random, unbiased approach to identify such genes...