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Article ; Online: Inducible CRISPR activation screen for interferon-stimulated genes identifies OAS1 as a SARS-CoV-2 restriction factor.

Danziger, Oded / Patel, Roosheel S / DeGrace, Emma J / Rosen, Mikaela R / Rosenberg, Brad R

2022 Volume 18, Issue 4, Page(s) e1010464

Abstract: Interferons establish an antiviral state through the induction of hundreds of interferon-stimulated genes (ISGs). The mechanisms and viral specificities for most ISGs remain incompletely understood. To enable high-throughput interrogation of ISG ... ...

Abstract	Interferons establish an antiviral state through the induction of hundreds of interferon-stimulated genes (ISGs). The mechanisms and viral specificities for most ISGs remain incompletely understood. To enable high-throughput interrogation of ISG antiviral functions in pooled genetic screens while mitigating potentially confounding effects of endogenous interferon and antiproliferative/proapoptotic ISG activities, we adapted a CRISPR-activation (CRISPRa) system for inducible ISG expression in isogenic cell lines with and without the capacity to respond to interferons. We used this platform to screen for ISGs that restrict SARS-CoV-2. Results included ISGs previously described to restrict SARS-CoV-2 and novel candidate antiviral factors. We validated a subset of these by complementary CRISPRa and cDNA expression experiments. OAS1, a top-ranked hit across multiple screens, exhibited strong antiviral effects against SARS-CoV-2, which required OAS1 catalytic activity. These studies demonstrate a high-throughput approach to assess antiviral functions within the ISG repertoire, exemplified by identification of multiple SARS-CoV-2 restriction factors.
MeSH term(s)	2',5'-Oligoadenylate Synthetase/genetics ; 2',5'-Oligoadenylate Synthetase/metabolism ; Antiviral Agents/pharmacology ; COVID-19/genetics ; Clustered Regularly Interspaced Short Palindromic Repeats ; Humans ; Interferons/metabolism ; SARS-CoV-2/genetics
Chemical Substances	Antiviral Agents ; Interferons (9008-11-1) ; OAS1 protein, human (EC 2.7.7.-) ; 2',5'-Oligoadenylate Synthetase (EC 2.7.7.84)
Language	English
Publishing date	2022-04-14
Publishing country	United States
Document type	Journal Article
ZDB-ID	2205412-1
ISSN	1553-7374 ; 1553-7374
ISSN (online)	1553-7374
ISSN	1553-7374
DOI	10.1371/journal.ppat.1010464
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: Interleukin-6 and Interferon-α Signaling

Danziger, Oded / Pupko, Tal / Bacharach, Eran / Ehrlich, Marcelo

Frontiers in immunology

2018 Volume 9, Page(s) 94

Abstract: Malignancy-induced alterations to cytokine signaling in tumor cells differentially regulate their interactions with the immune system and oncolytic viruses. The abundance of inflammatory cytokines in the tumor microenvironment suggests that such ... ...

Abstract	Malignancy-induced alterations to cytokine signaling in tumor cells differentially regulate their interactions with the immune system and oncolytic viruses. The abundance of inflammatory cytokines in the tumor microenvironment suggests that such signaling plays key roles in tumor development and therapy efficacy. The JAK-STAT axis transduces signals of interleukin-6 (IL-6) and interferons (IFNs), mediates antiviral responses, and is frequently altered in prostate cancer (PCa) cells. However, how activation of JAK-STAT signaling with different cytokines regulates interactions between oncolytic viruses and PCa cells is not known. Here, we employ LNCaP PCa cells, expressing (or not) JAK1, activated (or not) with IFNs (α or γ) or IL-6, and infected with RNA viruses of different oncolytic potential (EHDV-TAU, hMPV-GFP, or HIV-GFP) to address this matter. We show that in JAK1-expressing cells, IL-6 sensitized PCa cells to viral cell death in the presence or absence of productive infection, with dependence on virus employed. Contrastingly, IFNα induced a cytoprotective antiviral state. Biochemical and genetic (knockout) analyses revealed dependency of antiviral state or cytoprotection on STAT1 or STAT2 activation, respectively. In IL-6-treated cells, STAT3 expression was required for anti-proliferative signaling. Quantitative proteomics (SILAC) revealed a core repertoire of antiviral IFN-stimulated genes, induced by IL-6 or IFNs. Oncolysis in the absence of productive infection, induced by IL-6, correlated with reduction in regulators of cell cycle and metabolism. These results call for matching the viral features of the oncolytic agent, the malignancy-induced genetic-epigenetic alterations to JAK/STAT signaling and the cytokine composition of the tumor microenvironment for efficient oncolytic virotherapy.
MeSH term(s)	Animals ; Antiviral Agents/pharmacology ; Biomarkers ; Cell Line ; Gene Expression ; Gene Expression Regulation, Neoplastic ; Host-Pathogen Interactions ; Humans ; Interferon-alpha/metabolism ; Interferon-alpha/pharmacology ; Interleukin-6/metabolism ; Janus Kinase 1/metabolism ; Male ; Oncolytic Viruses/drug effects ; Oncolytic Viruses/physiology ; Prostatic Neoplasms/genetics ; Prostatic Neoplasms/metabolism ; Prostatic Neoplasms/pathology ; Proteome ; STAT Transcription Factors/genetics ; STAT Transcription Factors/metabolism ; STAT3 Transcription Factor/genetics ; STAT3 Transcription Factor/metabolism ; Signal Transduction ; Virus Diseases/immunology ; Virus Diseases/metabolism ; Virus Diseases/virology
Chemical Substances	Antiviral Agents ; Biomarkers ; Interferon-alpha ; Interleukin-6 ; Proteome ; STAT Transcription Factors ; STAT3 Transcription Factor ; Janus Kinase 1 (EC 2.7.10.2)
Language	English
Publishing date	2018-01-30
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2606827-8
ISSN	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2018.00094
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Article: Unambiguous detection of SARS-CoV-2 subgenomic mRNAs with single cell RNA sequencing.

Cohen, Phillip / DeGrace, Emma J / Danziger, Oded / Patel, Roosheel S / Barrall, Erika A / Bobrowski, Tesia / Kehrer, Thomas / Cupic, Anastasija / Miorin, Lisa / García-Sastre, Adolfo / Rosenberg, Brad R

bioRxiv : the preprint server for biology

2023

Abstract: Single cell RNA sequencing (scRNA-Seq) studies have provided critical insight into the pathogenesis of Severe Acute Respiratory Syndrome CoronaVirus 2 (SARS-CoV-2), the causative agent of COronaVIrus Disease 2019 (COVID-19). scRNA-Seq workflows are ... ...

Abstract	Single cell RNA sequencing (scRNA-Seq) studies have provided critical insight into the pathogenesis of Severe Acute Respiratory Syndrome CoronaVirus 2 (SARS-CoV-2), the causative agent of COronaVIrus Disease 2019 (COVID-19). scRNA-Seq workflows are generally designed for the detection and quantification of eukaryotic host mRNAs and not viral RNAs. Here, we compare different scRNA-Seq methods for their ability to quantify and detect SARS-CoV-2 RNAs with a focus on subgenomic mRNAs (sgmRNAs). We present a data processing strategy, single cell CoronaVirus sequencing (scCoVseq), which quantifies reads unambiguously assigned to sgmRNAs or genomic RNA (gRNA). Compared to standard 10X Genomics Chromium Next GEM Single Cell 3' (10X 3') and Chromium Next GEM Single Cell V(D)J (10X 5') sequencing, we find that 10X 5' with an extended read 1 (R1) sequencing strategy maximizes the detection of sgmRNAs by increasing the number of unambiguous reads spanning leader-sgmRNA junction sites. Using this method, we show that viral gene expression is highly correlated across cells suggesting a relatively consistent proportion of viral sgmRNA production throughout infection. Our method allows for quantification of coronavirus sgmRNA expression at single-cell resolution, and thereby supports high resolution studies of the dynamics of coronavirus RNA synthesis.
Language	English
Publishing date	2023-02-23
Publishing country	United States
Document type	Preprint
DOI	10.1101/2021.11.22.469642
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Article ; Online: Inducible CRISPR activation screen for interferon-stimulated genes identifies OAS1 as a SARS-CoV-2 restriction factor.

Oded Danziger / Roosheel S Patel / Emma J DeGrace / Mikaela R Rosen / Brad R Rosenberg

PLoS Pathogens, Vol 18, Iss 4, p e

2022 Volume 1010464

Abstract	Interferons establish an antiviral state through the induction of hundreds of interferon-stimulated genes (ISGs). The mechanisms and viral specificities for most ISGs remain incompletely understood. To enable high-throughput interrogation of ISG antiviral functions in pooled genetic screens while mitigating potentially confounding effects of endogenous interferon and antiproliferative/proapoptotic ISG activities, we adapted a CRISPR-activation (CRISPRa) system for inducible ISG expression in isogenic cell lines with and without the capacity to respond to interferons. We used this platform to screen for ISGs that restrict SARS-CoV-2. Results included ISGs previously described to restrict SARS-CoV-2 and novel candidate antiviral factors. We validated a subset of these by complementary CRISPRa and cDNA expression experiments. OAS1, a top-ranked hit across multiple screens, exhibited strong antiviral effects against SARS-CoV-2, which required OAS1 catalytic activity. These studies demonstrate a high-throughput approach to assess antiviral functions within the ISG repertoire, exemplified by identification of multiple SARS-CoV-2 restriction factors.
Keywords	Immunologic diseases. Allergy ; RC581-607 ; Biology (General) ; QH301-705.5
Language	English
Publishing date	2022-04-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Unambiguous detection of SARS-CoV-2 subgenomic mRNAs with single-cell RNA sequencing.

Cohen, Phillip / DeGrace, Emma J / Danziger, Oded / Patel, Roosheel S / Barrall, Erika A / Bobrowski, Tesia / Kehrer, Thomas / Cupic, Anastija / Miorin, Lisa / García-Sastre, Adolfo / Rosenberg, Brad R

Microbiology spectrum

2023 , Page(s) e0077623

Abstract: Single-cell RNA sequencing (scRNA-Seq) studies have provided critical insight into the pathogenesis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19). scRNA-Seq library preparation ...

Abstract	Single-cell RNA sequencing (scRNA-Seq) studies have provided critical insight into the pathogenesis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19). scRNA-Seq library preparation methods and data processing workflows are generally designed for the detection and quantification of eukaryotic host mRNAs and not viral RNAs. Here, we compare different scRNA-Seq library preparation methods for their ability to quantify and detect SARS-CoV-2 RNAs with a focus on subgenomic mRNAs (sgmRNAs). We show that compared to 10X Genomics Chromium Next GEM Single Cell 3' (10X 3') libraries or 10X Genomics Chromium Next GEM Single Cell V(D)J (10X 5') libraries sequenced with standard read configurations, 10X 5' libraries sequenced with an extended length read 1 (R1) that covers both cell barcode and transcript sequence (termed "10X 5' with extended R1") increase the number of unambiguous reads spanning leader-sgmRNA junction sites. We further present a data processing workflow, single-cell coronavirus sequencing (scCoVseq), which quantifies reads unambiguously assigned to viral sgmRNAs or viral genomic RNA (gRNA). We find that combining 10X 5' with extended R1 library preparation/sequencing and scCoVseq data processing maximizes the number of viral UMIs per cell quantified by scRNA-Seq. Corresponding sgmRNA expression levels are highly correlated with expression in matched bulk RNA-Seq data sets quantified with established tools for SARS-CoV-2 analysis. Using this scRNA-Seq approach, we find that SARS-CoV-2 gene expression is highly correlated across individual infected cells, which suggests that the proportion of viral sgmRNAs remains generally consistent throughout infection. Taken together, these results and corresponding data processing workflow enable robust quantification of coronavirus sgmRNA expression at single-cell resolution, thereby supporting high-resolution studies of viral RNA processes in individual cells. IMPORTANCE Single-cell RNA sequencing (scRNA-Seq) has emerged as a valuable tool to study host-virus interactions, especially for coronavirus disease 2019 (COVID-19). Here we compare the performance of different scRNA-Seq library preparation methods and sequencing strategies to detect SARS-CoV-2 RNAs and develop a data processing workflow to quantify unambiguous sequence reads derived from SARS-CoV-2 genomic RNA and subgenomic mRNAs. After establishing a workflow that maximizes the detection of SARS-CoV-2 subgenomic mRNAs, we explore patterns of SARS-CoV-2 gene expression across cells with variable levels of total viral RNA, assess host gene expression differences between infected and bystander cells, and identify non-canonical and lowly abundant SARS-CoV-2 RNAs. The sequencing and data processing strategies developed here can enhance studies of coronavirus RNA biology at single-cell resolution and thereby contribute to our understanding of viral pathogenesis.
Language	English
Publishing date	2023-09-07
Publishing country	United States
Document type	Journal Article
ZDB-ID	2807133-5
ISSN	2165-0497 ; 2165-0497
ISSN (online)	2165-0497
ISSN	2165-0497
DOI	10.1128/spectrum.00776-23
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Article ; Online: SARS-CoV-2 hijacks p38β/MAPK11 to promote virus replication.

Higgins, Christina A / Nilsson-Payant, Benjamin E / Bonaventure, Boris / Kurland, Andrew P / Ye, Chengjin / Yaron, Tomer M / Johnson, Jared L / Adhikary, Prithy / Golynker, Ilona / Panis, Maryline / Danziger, Oded / Rosenberg, Brad R / Cantley, Lewis C / Martínez-Sobrido, Luis / tenOever, Benjamin / Johnson, Jeffrey R

mBio

2023 Volume 14, Issue 4, Page(s) e0100723

Abstract: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of the coronavirus disease 2019 (COVID-19) pandemic, drastically modifies infected cells to optimize virus replication. One such modification is the activation of the host ... ...

Abstract	Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of the coronavirus disease 2019 (COVID-19) pandemic, drastically modifies infected cells to optimize virus replication. One such modification is the activation of the host p38 mitogen-activated protein kinase (MAPK) pathway, which plays a major role in inflammatory cytokine production, a hallmark of severe COVID-19. We previously demonstrated that inhibition of p38/MAPK activity in SARS-CoV-2-infected cells reduced both cytokine production and viral replication. Here, we combined quantitative genetic screening, genomics, proteomics, and phosphoproteomics to better understand mechanisms underlying the dependence of SARS-CoV-2 on the p38 pathway. We found that p38β is a critical host factor for SARS-CoV-2 replication in multiple relevant cell lines and that it functions at a step after viral mRNA expression. We identified putative host and viral p38β substrates in the context of SARS-CoV-2 infection and found that most host substrates have intrinsic antiviral activities. Taken together, this study reveals a unique proviral function for p38β and supports exploring p38β inhibitor development as a strategy toward creating a new class of COVID-19 therapies. IMPORTANCE SARS-CoV-2 is the causative agent of the COVID-19 pandemic that has claimed millions of lives since its emergence in 2019. SARS-CoV-2 infection of human cells requires the activity of several cellular pathways for successful replication. One such pathway, the p38 MAPK pathway, is required for virus replication and disease pathogenesis. Here, we applied systems biology approaches to understand how MAPK pathways benefit SARS-CoV-2 replication to inform the development of novel COVID-19 drug therapies.
MeSH term(s)	Humans ; COVID-19 ; Cytokines ; p38 Mitogen-Activated Protein Kinases/metabolism ; Pandemics ; SARS-CoV-2/metabolism ; Virus Replication ; Mitogen-Activated Protein Kinase 11/metabolism
Chemical Substances	Cytokines ; p38 Mitogen-Activated Protein Kinases (EC 2.7.11.24) ; Mitogen-Activated Protein Kinase 11 (EC 2.7.11.24)
Language	English
Publishing date	2023-06-22
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2557172-2
ISSN	2150-7511 ; 2161-2129
ISSN (online)	2150-7511
ISSN	2161-2129
DOI	10.1128/mbio.01007-23
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Article ; Online: Unambiguous detection of SARS-CoV-2 subgenomic mRNAs with single cell RNA sequencing

Cohen, Phillip / DeGrace, Emma J / Danziger, Oded / Patel, Roosheel / Rosenberg, Brad R

bioRxiv

Abstract: Single cell RNA sequencing (scRNAseq) studies have provided critical insight into the pathogenesis of Severe Acute Respiratory Syndrome CoronaVirus 2 (SARS-CoV-2), the causative agent of COronaVIrus Disease 2019 (COVID-19). scRNAseq workflows are ... ...

Abstract	Single cell RNA sequencing (scRNAseq) studies have provided critical insight into the pathogenesis of Severe Acute Respiratory Syndrome CoronaVirus 2 (SARS-CoV-2), the causative agent of COronaVIrus Disease 2019 (COVID-19). scRNAseq workflows are generally designed for the detection and quantification of eukaryotic host mRNAs and not viral RNAs. The performance of different scRNAseq methods to study SARS-CoV-2 RNAs has not been thoroughly evaluated. Here, we compare different scRNAseq methods for their ability to quantify and detect SARS-CoV-2 RNAs with a focus on subgenomic mRNAs (sgmRNAs), which are produced only during active viral replication and not present in viral particles. We present a data processing strategy, single cell CoronaVirus sequencing (scCoVseq), which quantifies reads unambiguously assigned to sgmRNAs or genomic RNA (gRNA). Compared to standard 10X Genomics Chromium Next GEM Single Cell 3′ (10X 3′) and Chromium Next GEM Single Cell V(D)J (10X 5′) sequencing, we find that 10X 5′ with an extended R1 sequencing strategy maximizes the unambiguous detection of sgmRNAs by increasing the number of reads spanning leader-sgmRNA junction sites. Differential gene expression testing and KEGG enrichment analysis of infected cells compared with bystander or mock cells showed an enrichment for COVID19-associated genes, supporting the ability of our method to accurately identify infected cells. Our method allows for quantification of coronavirus sgmRNA expression at single-cell resolution, and thereby supports high resolution studies of the dynamics of coronavirus RNA synthesis.
Keywords	covid19
Language	English
Publishing date	2021-11-24
Publisher	Cold Spring Harbor Laboratory
Document type	Article ; Online
DOI	10.1101/2021.11.22.469642
Database	COVID19

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Article ; Online: Inducible CRISPR activation screen for interferon-stimulated genes identifies OAS1 as a SARS-CoV-2 restriction factor

Danziger, Oded / Patel, Roosheel S / DeGrace, Emma J / Rosen, Mikaela R / Rosenberg, Brad R

bioRxiv

Abstract: Interferons establish an antiviral state in responding cells through the induction of hundreds of interferon-stimulated genes (ISGs). ISGs antagonize viral pathogens directly through diverse mechanisms acting at different stages of viral life cycles, and ...

Abstract	Interferons establish an antiviral state in responding cells through the induction of hundreds of interferon-stimulated genes (ISGs). ISGs antagonize viral pathogens directly through diverse mechanisms acting at different stages of viral life cycles, and indirectly by modulating cell cycle and promoting programmed cell death. The mechanisms of action and viral specificities for most ISGs remain incompletely understood. To enable the high throughput interrogation of ISG antiviral functions in pooled genetic screens while mitigating the potentially confounding effects of endogenous IFN and potential antiproliferative/proapoptotic ISG activities, we adapted a CRISPR-activation (CRISPRa) system for inducible ISG induction in isogenic cell lines with and without the capacity to respond to IFN. Engineered CRISPRa cell lines demonstrated inducible, robust, and specific gRNA-directed expression of ISGs, which are functional in restricting viral infection. Using this platform, we screened for ISGs that restrict SARS-CoV-2, the causative agent of the COVID-19 pandemic. Results included ISGs previously described to restrict SARS-CoV-2 as well as multiple novel candidate antiviral factors. We validated a subset of candidate hits by complementary targeted CRISPRa and ectopic cDNA expression infection experiments, which, among other hits, confirmed OAS1 as a SARS-CoV-2 restriction factor. OAS1 exhibited strong antiviral effects against SARS-CoV-2, and these effects required OAS1 catalytic activity. These studies demonstrate a robust, high-throughput approach to assess antiviral functions within the ISG repertoire, exemplified by the identification of multiple novel SARS-CoV-2 restriction factors.
Keywords	covid19
Language	English
Publishing date	2021-09-23
Publisher	Cold Spring Harbor Laboratory
Document type	Article ; Online
DOI	10.1101/2021.09.22.461286
Database	COVID19

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Article ; Online: Pediatrician, watch out for corona-phobia.

Rosenberg Danziger, Chen / Krause, Irit / Scheuerman, Oded / Luder, Anthony / Yulevich, Alon / Dalal, Ilan / Grisaru-Soen, Galia / Bilavsky, Efraim

European journal of pediatrics

2020 Volume 180, Issue 1, Page(s) 201–206

Abstract: The current outbreak of COVID-19 raging globally is taking a heavy toll on the adult population, with a rapidly growing number of newly infected and critically ill patients. However, to date, mortality rate among children is low as they mostly suffer ... ...

Abstract	The current outbreak of COVID-19 raging globally is taking a heavy toll on the adult population, with a rapidly growing number of newly infected and critically ill patients. However, to date, mortality rate among children is low as they mostly suffer from a mild disease. Yet, other more routinely encountered childhood diseases do not stand still and continue to be the main share of pediatricians' everyday challenges. Here we describe a case series of routinely seen pediatric diseases with delayed diagnosis due to different aspects of what we call "Corona-phobia". These cases were easily collected within a 1-week period which implies that this is a more widespread phenomenon.In conclusion, this raises the possibility that measures taken to mitigate this pandemic may be more damaging to children overall than the virus itself. We believe that pediatricians as well as policy makers should take this important aspect into consideration. What is Known: • COVID-19 manifests as a mild disease in most children; however, children are an important reservoir and may become spreaders of the disease. • Social distancing and isolation are important tools in mitigating COVID-19 transmission. What is New: • This case series describes 7 cases with delayed diagnosis of every-day pediatric diseases that were not caused by COVID-19 but were highly influenced by different aspects of "Corona-phobia". • Our objective is to highlight the possibility that measures taken to mitigate this pandemic may lead to a substantial delay in the diagnosis of other non-COVID-19 related diseases.
MeSH term(s)	Adolescent ; COVID-19/epidemiology ; Child ; Child, Preschool ; Female ; Humans ; Incidence ; Infant, Newborn ; Male ; Occupational Exposure/adverse effects ; Pandemics ; Pediatricians/psychology ; Phobic Disorders/epidemiology ; Phobic Disorders/etiology ; Phobic Disorders/psychology ; SARS-CoV-2
Keywords	covid19
Language	English
Publishing date	2020-07-13
Publishing country	Germany
Document type	Journal Article
ZDB-ID	194196-3
ISSN	1432-1076 ; 0340-6199 ; 0943-9676
ISSN (online)	1432-1076
ISSN	0340-6199 ; 0943-9676
DOI	10.1007/s00431-020-03736-y
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Article ; Online: Combined genetic and epigenetic interferences with interferon signaling expose prostate cancer cells to viral infection.

Danziger, Oded / Shai, Ben / Sabo, Yosef / Bacharach, Eran / Ehrlich, Marcelo

Oncotarget

2016 Volume 7, Issue 32, Page(s) 52115–52134

Abstract: Interferons (IFNs) induce anti-viral programs, regulate immune responses, and exert anti-proliferative effects. To escape anti-tumorigenic effects of IFNs, malignant cells attenuate JAK/STAT signaling and expression of IFN stimulated genes (ISGs). Such ... ...

Abstract	Interferons (IFNs) induce anti-viral programs, regulate immune responses, and exert anti-proliferative effects. To escape anti-tumorigenic effects of IFNs, malignant cells attenuate JAK/STAT signaling and expression of IFN stimulated genes (ISGs). Such attenuation may enhance the susceptibility of tumor cells to oncolytic virotherapy. Here we studied genetic and epigenetic mechanisms of interference with JAK/STAT signaling and their contribution to susceptibility of prostate cancer cells to viral infection. Bioinformatics analysis of gene-expression in cohorts of prostate cancer patients revealed genetic and epigenetic interference with the IFN program. To correlate lack of IFN signaling and susceptibility to viral infection and oncolysis; we employed LNCaP prostate cancer cells as cellular model, and the human metapneumovirus and the epizootic hemorrhagic disease virus as infectious agents. In LNCaP cells, JAK1 is silenced by bi-allelic inactivating mutations and epigenetic silencing, which also silences ISGs. Chemical inhibition of epigenetic silencing partially restored IFN-sensitivity, induced low levels of expression of selected ISGs and attenuated, but failed to block, viral infection and oncolysis. Since viral infection was not blocked by epigenetic modifiers, and these compounds may independently-induce anti-tumor effects, we propose that epigenetic modifiers and virotherapy are compatible in treatment of prostate tumors defective in JAK1 expression and IFN signaling.
Language	English
Publishing date	2016-08-09
Publishing country	United States
Document type	Journal Article
ZDB-ID	2560162-3
ISSN	1949-2553 ; 1949-2553
ISSN (online)	1949-2553
ISSN	1949-2553
DOI	10.18632/oncotarget.10313
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