Dissecting HSV-1-induced host shut-off at RNA level

Herpes simplex virus 1 (HSV-1) installs a profound host shut-off during lytic infection. The virion host shut-off (vhs) protein plays a key role in this process by efficiently cleaving both host and viral mRNAs in a translation-initiation-dependent manner. Furthermore, the onset of viral DNA replication is accompanied by a rapid decline in transcriptional activity of the host genome. Both mechanisms have tremendous impact on the RNA expression profile of the infected cells. To dissect their relative contributions and elucidate gene-specific host transcriptional responses throughout the first 8h of lytic HSV-1 infection, we here employed RNA-seq of total, newly transcribed (4sU-labelled) and chromatin-associated RNA in wild-type (WT) and Δvhs infection of primary human fibroblasts. Following virus entry, vhs activity rapidly plateaued at an elimination rate of around 30% of cellular mRNAs per hour until 8h p.i. In parallel, host transcriptional activity dropped down to 10-20%. While the combined effects of both phenomena dominated infection-induced changes in total RNA, extensive gene-specific transcriptional regulation was observable in chromatin-associated RNA. This was surprisingly concordant between WT HSV-1 and its Δvhs mutant and at least in parts mediated by the embryonic transcription factor DUX4. Furthermore, both WT and Δvhs infection induced strong transcriptional up-regulation of a small subset of genes. Most of these were either poorly or not at all expressed prior to infection but already primed by H3K4me3 histone marks at their promoters. Most interestingly, analysis of chromatin-associated RNA revealed vhs-nuclease-activity-dependent transcriptional down-regulation of at least 150 cellular genes, in particular of many genes encoding integrin adhesome and extracellular matrix components. This was accompanied by a vhs-dependent reduction in protein levels by 8h p.i. for many of these genes. In summary, our study provides a comprehensive picture of the molecular mechanisms that govern cellular RNA metabolism during the first 8h of lytic HSV-1 infection

Dissecting herpes simplex virus 1-induced host shutoff at the RNA level

Herpes simplex virus 1 (HSV-1) induces a profound host shut-off during lytic infection. The virion host shut-off (vhs) protein plays a key role in this process by efficiently cleaving host and viral mRNAs. Furthermore, the onset of viral DNA replication is accompanied by a rapid decline in host transcriptional activity. To dissect relative contributions of both mechanisms and elucidate gene-specific host transcriptional responses throughout the first 8h of lytic HSV-1 infection, we employed RNA-seq of total, newly transcribed (4sU-labelled) and chromatin-associated RNA in wild-type (WT) and Δvhs infection of primary human fibroblasts. Following virus entry, vhs activity rapidly plateaued at an elimination rate of around 30% of cellular mRNAs per hour until 8h p.i. In parallel, host transcriptional activity dropped to 10-20%. While the combined effects of both phenomena dominated infection-induced changes in total RNA, extensive gene-specific transcriptional regulation was observable in chromatin-associated RNA and was surprisingly concordant between WT and Δvhs infection. Both induced strong transcriptional up-regulation of a small subset of genes that were poorly expressed prior to infection but already primed by H3K4me3 histone marks at their promoters. Most interestingly, analysis of chromatin-associated RNA revealed vhs-nuclease-activity-dependent transcriptional down-regulation of at least 150 cellular genes, in particular of many integrin adhesome and extracellular matrix components. This was accompanied by a vhs-dependent reduction in protein levels by 8h p.i. for many of these genes. In summary, our study provides a comprehensive picture of the molecular mechanisms that govern cellular RNA metabolism during the first 8h of lytic HSV-1 infection. IMPORTANCE: The HSV-1 virion host shut-off (vhs) protein efficiently cleaves both host and viral mRNAs in a translation-dependent manner. In this study, we model and quantify changes in vhs activity as well as virus-induced global loss of host transcriptional activity during productive HSV-1 infection. In general, HSV-1-induced alterations in total RNA levels were dominated by these two global effects. In contrast, chromatin-associated RNA depicted gene-specific transcriptional changes. This revealed highly concordant transcriptional changes in WT and Δvhs infection, confirmed DUX4 as a key transcriptional regulator in HSV-1 infection and depicted vhs-dependent, transcriptional down-regulation of the integrin adhesome and extracellular matrix components. The latter explained seemingly gene-specific effects previously attributed to vhs-mediated mRNA degradation and resulted in a concordant loss in protein levels by 8h p.i. for many of the respective genes

Search for W' bosons decaying to an electron and a neutrino with the D0 detector

This Letter describes the search for a new heavy charged gauge boson W' decaying into an electron and a neutrino. The data were collected with the D0 detector at the Fermilab Tevatron proton-antiproton Collider at a center-of-mass energy of 1.96 TeV, and correspond to an integrated luminosity of about 1 inverse femtobarn. Lacking any significant excess in the data in comparison with known processes, an upper limit is set on the production cross section times branching fraction, and a W' boson with mass below 1.00 TeV can be excluded at the 95% C.L., assuming standard-model-like couplings to fermions. This result significantly improves upon previous limits, and is the most stringent to date.Comment: submitted to Phys. Rev. Let

Measurement of the ratios of the Z/G* + >= n jet production cross sections to the total inclusive Z/G* cross section in ppbar collisions at sqrt(s) = 1.96 TeV

We present a study of events with Z bosons and jets produced at the Fermilab Tevatron Collider in ppbar collisions at a center of mass energy of 1.96 TeV. The data sample consists of nearly 14,000 Z/G* -> e+e- candidates corresponding to the integrated luminosity of 0.4 fb-1 collected using the D0 detector. Ratios of the Z/G* + >= n jet cross sections to the total inclusive Z/G* cross section have been measured for n = 1 to 4 jet events. Our measurements are found to be in good agreement with a next-to-leading order QCD calculation and with a tree-level QCD prediction with parton shower simulation and hadronization.Comment: 7 pages, 2 figures, slightly modified, submitted to Phys. Lett.

Search for the associated production of a b quark and a neutral supersymmetric Higgs boson which decays to tau pairs

We report results from a search for production of a neutral Higgs boson in association with a $b$ quark. We search for Higgs decays to $\tau$ pairs with one $\tau$ subsequently decaying to a muon and the other to hadrons. The data correspond to 2.7fb$^{-1}$ of \ppbar collisions recorded by the D0 detector at $\sqrt{s} = 1.96$TeV. The data are found to be consistent with background predictions. The result allows us to exclude a significant region of parameter space of the minimal supersymmetric model.Comment: Submitted to Phys. Rev. Letter

The bimodal absorption system imaging campaign (BASIC). I. A dual population of low-metallicity absorbers at z < 1

Instrumentatio

Search for Supersymmetry in Di-Photon Final States at sqrt{s} = 1.96 TeV

We report results of a search for supersymmetry (SUSY) with gauge-mediated symmetry breaking in di-photon events collected by the D0 experiment at the Fermilab Tevatron Collider in 2002--2006. In 1.1 fb$^{-1}$ of data, we find no significant excess beyond the background expected from the standard model and set the most stringent lower limits to date for a standard benchmark model on the lightest neutralino and chargino masses of 125 GeV and 229 GeV, respectively, at 95% confidence

Search for squarks and gluinos in events with jets and missing transverse energy using 2.1 fb-1 of ppbar collision data at sqrt(s)=1.96 TeV

A data sample corresponding to an integrated luminosity of 2.1 fb-1 collected by the D0 detector at the Fermilab Tevatron Collider was analyzed to search for squarks and gluinos produced in ppbar collisions at a center-of-mass energy of 1.96 TeV. No evidence for the production of such particles was observed in topologies involving jets and missing transverse energy, and 95% C.L. lower limits of 379 GeV and 308 GeV were set on the squark and gluino masses, respectively, within the framework of minimal supergravity with tan(beta)=3, A0=0, and mu<0. The corresponding previous limits are improved by 54 GeV and 67 GeV

Search for the lightest scalar top quark in events with two leptons in p-pbar collisions at sqrt(s) = 1.96 TeV

Data collected by the D0 detector at a p-pbar center-of-mass energy of 1.96 TeV at the Fermilab Tevatron Collider have been used to search for pair production of the lightest supersymmetric partner of the top quark decaying into $b \ell \tilde{\nu}$. The search is performed in the $\ell\ell' = e\mu$ and $\mu \mu$ final states. No evidence for this process has been found in data samples of approximately 400 pb^-1. The domain in the [$M(\tilde{t}_1),M(\tilde{\nu})$] plane excluded at the 95% C.L. is substantially extended by this search.Comment: 9 pages, 11 figures. Selection-cut layouts slightly different than in PL