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Article ; Online: Chaperonin TRiC/CCT Participates in Mammarenavirus Multiplication in Human Cells via Interaction with the Viral Nucleoprotein.

Sakabe, Saori / Witwit, Haydar / Khafaji, Roaa / Cubitt, Beatrice / de la Torre, Juan C

2023 Volume 97, Issue 2, Page(s) e0168822

Abstract: The eukaryotic chaperonin containing tailless complex polypeptide 1 ring complex (CCT, also known as TCP-1 Ring Complex, TRiC/CCT) participates in the folding of 5% to 10% of the cellular proteome and has been involved in the life cycle of several ... ...

Abstract	The eukaryotic chaperonin containing tailless complex polypeptide 1 ring complex (CCT, also known as TCP-1 Ring Complex, TRiC/CCT) participates in the folding of 5% to 10% of the cellular proteome and has been involved in the life cycle of several viruses, including dengue, Zika, and influenza viruses, but the mechanisms by which the TRiC/CCT complex contributes to virus multiplication remain poorly understood. Here, we document that the nucleoprotein (NP) of the mammarenavirus lymphocytic choriomeningitis virus (LCMV) is a substrate of the human TRiC/CCT complex, and that pharmacological inhibition of TRiC/CCT complex function, or RNAi-mediated knockdown of TRiC/CCT complex subunits, inhibited LCMV multiplication in human cells. We obtained evidence that the TRiC/CCT complex is required for the production of NP-containing virus-like particles (VLPs), and the activity of the virus ribonucleoprotein (vRNP) responsible for directing replication and transcription of the viral genome. Pharmacological inhibition of the TRIC/CCT complex also restricted multiplication of the live-attenuated vaccine candidates Candid#1 and ML29 of the hemorrhagic fever causing Junin (JUNV) and Lassa (LASV) mammarenaviruses, respectively. Our findings indicate that the TRiC/CCT complex is required for mammarenavirus multiplication and is an attractive candidate for the development of host directed antivirals against human-pathogenic mammarenaviruses.
MeSH term(s)	Humans ; Antiviral Agents ; Chaperonin Containing TCP-1/metabolism ; Lymphocytic choriomeningitis virus ; Nucleoproteins ; Virus Replication
Chemical Substances	Antiviral Agents ; Chaperonin Containing TCP-1 (EC 3.6.1.-) ; Nucleoproteins
Language	English
Publishing date	2023-01-19
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	80174-4
ISSN	1098-5514 ; 0022-538X
ISSN (online)	1098-5514
ISSN	0022-538X
DOI	10.1128/jvi.01688-22
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Article: Functional impairment of "helpless" CD8

van der Heide, Verena / Davenport, Bennett / Cubitt, Beatrice / Roudko, Vladimir / Choo, Daniel / Humblin, Etienne / Jhun, Kevin / Angeliadis, Krista / Dawson, Travis / Furtado, Glaucia / Kamphorst, Alice / Ahmed, Rafi / de la Torre, Juan Carlos / Homann, Dirk

bioRxiv : the preprint server for biology

2024

Abstract: Generation of functional ... ...

Abstract	Generation of functional CD8
Language	English
Publishing date	2024-01-26
Publishing country	United States
Document type	Preprint
DOI	10.1101/2024.01.22.576725
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Article ; Online: Molecular Engineering of a Mammarenavirus with Unbreachable Attenuation.

Sakabe, Saori / Cubitt, Beatrice / Martinez-Sobrido, Luis / de la Torre, Juan C

Journal of virology

2022 Volume 97, Issue 1, Page(s) e0138522

Abstract: Several mammarenaviruses cause severe hemorrhagic fever (HF) disease in humans and pose important public health problems in their regions of endemicity. There are no United States (US) Food and Drug Administration (FDA)-approved mammarenavirus vaccines, ... ...

Abstract	Several mammarenaviruses cause severe hemorrhagic fever (HF) disease in humans and pose important public health problems in their regions of endemicity. There are no United States (US) Food and Drug Administration (FDA)-approved mammarenavirus vaccines, and current anti-mammarenavirus therapy is limited to an off-label use of ribavirin that has limited efficacy. Mammarenaviruses are enveloped viruses with a bi-segmented negative-strand RNA genome. Each genome segment contains two open reading frames (ORF) separated by a noncoding intergenic region (IGR). The large (L) segment encodes the RNA dependent RNA polymerase, L protein, and the Z matrix protein, whereas the small (S) segment encodes the surface glycoprotein precursor (GPC) and nucleoprotein (NP). In the present study, we document the generation of a recombinant form of the prototypic mammarenavirus lymphocytic choriomeningitis virus (LCMV) expressing a codon deoptimized (CD) GPC and containing the IGR of the S segment in both the S and L segments (rLCMV/IGR-CD). We show that rLCMV/IGR-CD is fully attenuated in C57BL/6 (B6) mice but able to provide complete protection upon a single administration against a lethal challenge with LCMV. Importantly, rLCMV/IGR-CD exhibited an unbreachable attenuation for its safe implementation as a live-attenuated vaccine (LAV).
MeSH term(s)	Animals ; Humans ; Mice ; Codon/genetics ; DNA, Intergenic/genetics ; Lymphocytic choriomeningitis virus/genetics ; Lymphocytic choriomeningitis virus/immunology ; Mice, Inbred C57BL ; Vaccines, Attenuated/immunology ; Genetic Engineering ; Viral Vaccines ; Vaccine Development
Chemical Substances	Codon ; DNA, Intergenic ; Vaccines, Attenuated ; Viral Vaccines
Language	English
Publishing date	2022-12-19
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	80174-4
ISSN	1098-5514 ; 0022-538X
ISSN (online)	1098-5514
ISSN	0022-538X
DOI	10.1128/jvi.01385-22
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Zs.A 609: Show issues

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ab Jg. 2022: Lesesaal (EG)

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Article ; Online: The Pan-ErbB tyrosine kinase inhibitor afatinib inhibits multiple steps of the mammarenavirus life cycle.

Mizuma, Keita / Takashima, Ayako / Cubitt, Beatrice / de la Torre, Juan C / Iwasaki, Masaharu

Virology

2022 Volume 576, Page(s) 83–95

Abstract: The mammarenavirus Lassa virus (LASV) causes a life-threatening acute febrile disease, Lassa fever (LF). To date, no US Food and Drug Administration (FDA)-licensed medical countermeasures against LASV are available. This underscores the need for the ... ...

Abstract	The mammarenavirus Lassa virus (LASV) causes a life-threatening acute febrile disease, Lassa fever (LF). To date, no US Food and Drug Administration (FDA)-licensed medical countermeasures against LASV are available. This underscores the need for the development of novel anti-LASV drugs. Here, we screen an FDA-approved drug library to identify novel anti-LASV drug candidates using an infectious-free cell line expressing a functional LASV ribonucleoprotein (vRNP), where levels of vRNP-directed reporter gene expression serve as a surrogate for vRNP activity. Our screen identified the pan-ErbB tyrosine kinase inhibitor afatinib as a potent inhibitor of LASV vRNP activity. Afatinib inhibited multiplication of lymphocytic choriomeningitis virus (LCMV) a mammarenavirus closely related to LASV. Cell-based assays revealed that afatinib inhibited multiple steps of the LASV and LCMV life cycles. Afatinib also inhibited multiplication of Junín virus vaccine strain Candid#1, indicating that afatinib can have antiviral activity against a broad range of human pathogenic mammarenaviruses.
MeSH term(s)	Chlorocebus aethiops ; Animals ; Humans ; Arenaviridae ; Afatinib ; Vero Cells ; Lassa virus/genetics ; Lassa Fever ; Lymphocytic choriomeningitis virus ; Antiviral Agents/pharmacology ; Ribonucleoproteins/metabolism ; Protein Kinase Inhibitors/pharmacology ; Life Cycle Stages ; Vaccines
Chemical Substances	Afatinib (41UD74L59M) ; Antiviral Agents ; Ribonucleoproteins ; Protein Kinase Inhibitors ; Vaccines
Language	English
Publishing date	2022-09-26
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	200425-2
ISSN	1096-0341 ; 0042-6822
ISSN (online)	1096-0341
ISSN	0042-6822
DOI	10.1016/j.virol.2022.09.005
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Article ; Online: Activation of protein kinase receptor (PKR) plays a pro-viral role in mammarenavirus-infected cells.

Witwit, Haydar / Khafaji, Roaa / Salaniwal, Arul / Kim, Arthur S / Cubitt, Beatrice / Jackson, Nathaniel / Ye, Chengjin / Weiss, Susan R / Martinez-Sobrido, Luis / de la Torre, Juan Carlos

Journal of virology

2024 Volume 98, Issue 3, Page(s) e0188323

Abstract: Many viruses, including mammarenaviruses, have evolved mechanisms to counteract different components of the host cell innate immunity, which is required to facilitate robust virus multiplication. The double-stranded RNA (dsRNA) sensor protein kinase ... ...

Abstract	Many viruses, including mammarenaviruses, have evolved mechanisms to counteract different components of the host cell innate immunity, which is required to facilitate robust virus multiplication. The double-stranded RNA (dsRNA) sensor protein kinase receptor (PKR) pathway plays a critical role in the cell anti-viral response. Whether PKR can restrict the multiplication of the Old World mammarenavirus lymphocytic choriomeningitis virus (LCMV) and the mechanisms by which LCMV may counteract the anti-viral functions of PKR have not yet been investigated. Here we present evidence that LCMV infection results in very limited levels of PKR activation, but LCMV multiplication is enhanced in the absence of PKR. In contrast, infection with a recombinant LCMV with a mutation affecting the 3'-5' exonuclease (ExoN) activity of the viral nucleoprotein resulted in robust PKR activation in the absence of detectable levels of dsRNA, which was associated with severely restricted virus multiplication that was alleviated in the absence of PKR. However, pharmacological inhibition of PKR activation resulted in reduced levels of LCMV multiplication. These findings uncovered a complex role of the PKR pathway in LCMV-infected cells involving both pro- and anti-viral activities.IMPORTANCEAs with many other viruses, the prototypic Old World mammarenavirus LCMV can interfere with the host cell innate immune response to infection, which includes the dsRNA sensor PKR pathway. A detailed understanding of LCMV-PKR interactions can provide novel insights about mammarenavirus-host cell interactions and facilitate the development of effective anti-viral strategies against human pathogenic mammarenaviruses. In the present work, we present evidence that LCMV multiplication is enhanced in PKR-deficient cells, but pharmacological inhibition of PKR activation unexpectedly resulted in severely restricted propagation of LCMV. Likewise, we document a robust PKR activation in LCMV-infected cells in the absence of detectable levels of dsRNA. Our findings have revealed a complex role of the PKR pathway during LCMV infection and uncovered the activation of PKR as a druggable target for the development of anti-viral drugs against human pathogenic mammarenaviruses.
MeSH term(s)	Humans ; Arenaviridae/metabolism ; Cell Line ; Protein Kinases/metabolism ; Host-Pathogen Interactions ; Lymphocytic choriomeningitis virus/metabolism ; Carrier Proteins ; Lymphocytic Choriomeningitis ; Antiviral Agents ; eIF-2 Kinase/genetics ; eIF-2 Kinase/metabolism
Chemical Substances	Protein Kinases (EC 2.7.-) ; Carrier Proteins ; Antiviral Agents ; eIF-2 Kinase (EC 2.7.11.1)
Language	English
Publishing date	2024-02-20
Publishing country	United States
Document type	Journal Article
ZDB-ID	80174-4
ISSN	1098-5514 ; 0022-538X
ISSN (online)	1098-5514
ISSN	0022-538X
DOI	10.1128/jvi.01883-23
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Zs.A 609: Show issues

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Je nach Verfügbarkeit (siehe Angabe bei Bestand)
bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
Jg. 1995 - 2021: Lesesall (1.OG)
ab Jg. 2022: Lesesaal (EG)

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Article ; Online: Lassa Virus Vaccine Candidate ML29 Generates Truncated Viral RNAs Which Contribute to Interfering Activity and Attenuation.

Johnson, Dylan M / Cubitt, Beatrice / Pfeffer, Tia L / de la Torre, Juan Carlos / Lukashevich, Igor S

Viruses

2021 Volume 13, Issue 2

Abstract: Defective interfering particles (DIPs) are naturally occurring products during virus replication in infected cells. DIPs contain defective viral genomes (DVGs) and interfere with replication and propagation of their corresponding standard viral genomes ... ...

Abstract	Defective interfering particles (DIPs) are naturally occurring products during virus replication in infected cells. DIPs contain defective viral genomes (DVGs) and interfere with replication and propagation of their corresponding standard viral genomes by competing for viral and cellular resources, as well as promoting innate immune antiviral responses. Consequently, for many different viruses, including mammarenaviruses, DIPs play key roles in the outcome of infection. Due to their ability to broadly interfere with viral replication, DIPs are attractive tools for the development of a new generation of biologics to target genetically diverse and rapidly evolving viruses. Here, we provide evidence that in cells infected with the Lassa fever (LF) vaccine candidate ML29, a reassortant that carries the nucleoprotein (NP) and glycoprotein (GP) dominant antigens of the pathogenic Lassa virus (LASV) together with the L polymerase and Z matrix protein of the non-pathogenic genetically related Mopeia virus (MOPV), L-derived truncated RNA species are readily detected following infection at low multiplicity of infection (MOI) or in persistently-infected cells originally infected at high MOI. In the present study, we show that expression of green fluorescent protein (GFP) driven by a tri-segmented form of the mammarenavirus lymphocytic choriomeningitis virus (r3LCMV-GFP/GFP) was strongly inhibited in ML29-persistently infected cells, and that the magnitude of GFP suppression was dependent on the passage history of the ML29-persistently infected cells. In addition, we found that DIP-enriched ML29 was highly attenuated in immunocompetent CBA/J mice and in Hartley guinea pigs. Likewise, STAT-1
MeSH term(s)	Animals ; Female ; Genome, Viral ; Guinea Pigs ; Humans ; Lassa Fever/genetics ; Lassa Fever/immunology ; Lassa Fever/prevention & control ; Lassa Fever/virology ; Lassa virus/genetics ; Lassa virus/immunology ; Lassa virus/physiology ; Mice ; Mice, Inbred CBA ; RNA, Viral/genetics ; RNA, Viral/immunology ; Viral Vaccines/administration & dosage ; Viral Vaccines/genetics ; Viral Vaccines/immunology ; Virus Replication
Chemical Substances	RNA, Viral ; Viral Vaccines
Language	English
Publishing date	2021-01-30
Publishing country	Switzerland
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2516098-9
ISSN	1999-4915 ; 1999-4915
ISSN (online)	1999-4915
ISSN	1999-4915
DOI	10.3390/v13020214
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Article: Inhibitors of anti-apoptotic Bcl-2 family proteins exhibit potent and broad-spectrum anti-mammarenavirus activity via cell cycle arrest at G0/G1 phase.

Kim, Yu-Jin / Witwit, Haydar / Cubitt, Beatrice / de la Torre, Juan C

bioRxiv : the preprint server for biology

2021

Abstract: Targeting host factors is a promising strategy to develop broad-spectrum antiviral drugs. Drugs targeting anti-apoptotic Bcl-2 family proteins that were originally developed as tumor suppressors have been reported to inhibit multiplication of different ... ...

Abstract	Targeting host factors is a promising strategy to develop broad-spectrum antiviral drugs. Drugs targeting anti-apoptotic Bcl-2 family proteins that were originally developed as tumor suppressors have been reported to inhibit multiplication of different types of viruses. However, the mechanisms whereby Bcl-2 inhibitors exert their antiviral activity remain poorly understood. In this study, we have investigated the mechanisms by which obatoclax (OLX) and ABT-737 Bcl-2 inhibitors exhibited a potent antiviral activity against the mammarenavirus lymphocytic choriomeningitis virus (LCMV). OLX and ABT-737 potent anti-LCMV activity was not associated with their pro-apoptotic properties, but rather their ability of inducing cell arrest at G0/G1 phase. OLX and ABT-737 mediated inhibition of Bcl-2 correlated with reduced expression levels of thymidine kinase 1 (TK1), cyclin A2 (CCNA2), and cyclin B1 (CCNB1) cell cycle regulators. In addition, siRNA-mediated knock down of TK1, CCNA2, and CCNB1 resulted in reduced levels of LCMV multiplication. The antiviral activity exerted by Bcl-2 inhibitors correlated with reduced levels of viral RNA synthesis at early times of infection. Importantly, ABT-737 exhibited moderate efficacy in a mouse model of LCMV infection, and Bcl-2 inhibitors displayed broad-spectrum antiviral activities against different mammarenaviruses and SARS-CoV-2. Our results suggest that Bcl-2 inhibitors, actively being explored as anti-cancer therapeutics, might be repositioned as broad-spectrum antivirals. Importance: Anti-apoptotic Bcl-2 inhibitors have been shown to exert potent antiviral activities against various types of viruses via mechanisms that are currently poorly understood. This study has revealed that Bcl-2 inhibitors mediated cell cycle arrest at the G0/G1 phase, rather than their pro-apoptotic activity, plays a critical role in blocking mammarenavirus multiplication in cultured cells. In addition, we show that Bcl-2 inhibitor ABT-737 exhibited moderate anti-mammarenavirus activity
Language	English
Publishing date	2021-08-17
Publishing country	United States
Document type	Preprint
DOI	10.1101/2021.08.16.456587
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Article ; Online: Inhibitors of Anti-apoptotic Bcl-2 Family Proteins Exhibit Potent and Broad-Spectrum Anti-mammarenavirus Activity via Cell Cycle Arrest at G0/G1 Phase.

Kim, Yu-Jin / Witwit, Haydar / Cubitt, Beatrice / de la Torre, Juan C

Journal of virology

2021 Volume 95, Issue 24, Page(s) e0139921

Abstract	Targeting host factors is a promising strategy to develop broad-spectrum antiviral drugs. Drugs targeting anti-apoptotic Bcl-2 family proteins that were originally developed as tumor suppressors have been reported to inhibit multiplication of different types of viruses. However, the mechanisms whereby Bcl-2 inhibitors exert their antiviral activity remain poorly understood. In this study, we have investigated the mechanisms by which obatoclax (OLX) and ABT-737 Bcl-2 inhibitors exhibited a potent antiviral activity against the mammarenavirus lymphocytic choriomeningitis virus (LCMV). OLX and ABT-737 potent anti-LCMV activity was not associated with their proapoptotic properties but rather with their ability to induce cell arrest at the G0/G1 phase. OLX- and ABT-737-mediated inhibition of Bcl-2 correlated with reduced expression levels of thymidine kinase 1 (TK1), cyclin A2 (CCNA2), and cyclin B1 (CCNB1) cell cycle regulators. In addition, small interfering RNA (siRNA)-mediated knockdown of TK1, CCNA2, and CCNB1 resulted in reduced levels of LCMV multiplication. The antiviral activity exerted by Bcl-2 inhibitors correlated with reduced levels of viral RNA synthesis at early times of infection. Importantly, ABT-737 exhibited moderate efficacy in a mouse model of LCMV infection, and Bcl-2 inhibitors displayed broad-spectrum antiviral activities against different mammarenaviruses and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Our results suggest that Bcl-2 inhibitors, actively being explored as anticancer therapeutics, might be repositioned as broad-spectrum antivirals.
MeSH term(s)	A549 Cells ; Animals ; Antiviral Agents/pharmacology ; Apoptosis ; Apoptosis Regulatory Proteins/pharmacology ; Arenaviridae/drug effects ; Biphenyl Compounds/pharmacology ; COVID-19/drug therapy ; COVID-19/virology ; Cell Cycle ; Cell Cycle Checkpoints/drug effects ; Cells, Cultured/drug effects ; Cells, Cultured/virology ; Chlorocebus aethiops ; Cyclin A2/biosynthesis ; Cyclin B1/biosynthesis ; G1 Phase ; Humans ; Indoles/pharmacology ; Mice ; Mice, Inbred C57BL ; Nitrophenols/pharmacology ; Piperazines/pharmacology ; Proto-Oncogene Proteins c-bcl-2/metabolism ; Pyrroles/pharmacology ; Resting Phase, Cell Cycle ; SARS-CoV-2 ; Sulfonamides/pharmacology ; Thymidine Kinase/biosynthesis ; Vero Cells
Chemical Substances	ABT-737 ; Antiviral Agents ; Apoptosis Regulatory Proteins ; BCL2 protein, human ; Biphenyl Compounds ; CCNA2 protein, human ; CCNA2 protein, mouse ; CCNB1 protein, human ; Ccnb1 protein, mouse ; Cyclin A2 ; Cyclin B1 ; Indoles ; Nitrophenols ; Piperazines ; Proto-Oncogene Proteins c-bcl-2 ; Pyrroles ; Sulfonamides ; Bcl2 protein, mouse (114100-40-2) ; Thymidine Kinase (EC 2.7.1.21) ; thymidine kinase 1 (EC 2.7.1.21) ; obatoclax (QN4128B52A)
Language	English
Publishing date	2021-09-29
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	80174-4
ISSN	1098-5514 ; 0022-538X
ISSN (online)	1098-5514
ISSN	0022-538X
DOI	10.1128/JVI.01399-21
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Zs.A 609: Show issues

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Jg. 1995 - 2021: Lesesall (1.OG)
ab Jg. 2022: Lesesaal (EG)

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Article: Activation of Protein Kinase R (PKR) Plays a Pro-Viral Role in Mammarenavirus Infected Cells.

Witwit, Haydar / Khafaji, Roaa / Salaniwal, Arul / Kim, Arthur S / Cubitt, Beatrice / Jackson, Nathaniel / Ye, Chengjin / Weiss, Susan R / Martinez-Sobrido, Luis / de la Torre, Juan Carlos

bioRxiv : the preprint server for biology

2023

Abstract: Many viruses, including mammarenaviruses, have evolved mechanisms to counteract different components of the host cell innate immunity, which is required to facilitate robust virus multiplication. The double strand (ds)RNA sensor protein kinase receptor ( ... ...

Abstract	Many viruses, including mammarenaviruses, have evolved mechanisms to counteract different components of the host cell innate immunity, which is required to facilitate robust virus multiplication. The double strand (ds)RNA sensor protein kinase receptor (PKR) pathway plays a critical role in the cell antiviral response. Whether PKR can restrict the multiplication of the Old World mammarenavirus lymphocytic choriomeningitis virus (LCMV) and the mechanisms by which LCMV may counteract the antiviral functions of PKR have not yet been investigated. Here we present evidence that LCMV infection results in very limited levels of PKR activation, but LCMV multiplication is enhanced in the absence of PKR. In contrast, infection with a recombinant LCMV with a mutation affecting the 3'-5' exonuclease (ExoN) activity of the viral nucleoprotein (NP) resulted in robust PKR activation in the absence of detectable levels of dsRNA, which was associated with severely restricted virus multiplication that was alleviated in the absence of PKR. However, pharmacological inhibition of PKR activation resulted in reduced levels of LCMV multiplication. These findings uncovered a complex role of the PKR pathway in LCMV-infected cells involving both pro-and antiviral activities.
Language	English
Publishing date	2023-12-06
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.12.05.570143
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Novel Dihydroorotate Dehydrogenase Inhibitors with Potent Interferon-Independent Antiviral Activity against Mammarenaviruses In Vitro.

Kim, Yu-Jin / Cubitt, Beatrice / Cai, Yingyun / Kuhn, Jens H / Vitt, Daniel / Kohlhof, Hella / de la Torre, Juan C

Viruses

2020 Volume 12, Issue 8

Abstract: Mammarenaviruses cause chronic infections in rodents, which are their predominant natural hosts. Human infection with some of these viruses causes high-consequence disease, posing significant issues in public health. Currently, no FDA-licensed ... ...

Abstract	Mammarenaviruses cause chronic infections in rodents, which are their predominant natural hosts. Human infection with some of these viruses causes high-consequence disease, posing significant issues in public health. Currently, no FDA-licensed mammarenavirus vaccines are available, and anti-mammarenavirus drugs are limited to an off-label use of ribavirin, which is only partially efficacious and associated with severe side effects. Dihydroorotate dehydrogenase (DHODH) inhibitors, which block
MeSH term(s)	Animals ; Antiviral Agents/pharmacology ; Arenaviridae/classification ; Arenaviridae/drug effects ; Arenaviridae/physiology ; Chlorocebus aethiops ; Dihydroorotate Dehydrogenase ; Drug Evaluation, Preclinical ; Enzyme Inhibitors/chemistry ; Enzyme Inhibitors/pharmacology ; HEK293 Cells ; Humans ; Interferons ; Mice ; Mice, Inbred C57BL ; Nucleic Acid Synthesis Inhibitors/chemistry ; Nucleic Acid Synthesis Inhibitors/pharmacology ; Oxidoreductases Acting on CH-CH Group Donors/antagonists & inhibitors ; Pyrimidines/biosynthesis ; Vero Cells ; Virus Replication/drug effects
Chemical Substances	Antiviral Agents ; Dihydroorotate Dehydrogenase ; Enzyme Inhibitors ; Nucleic Acid Synthesis Inhibitors ; Pyrimidines ; Interferons (9008-11-1) ; Oxidoreductases Acting on CH-CH Group Donors (EC 1.3.-) ; pyrimidine (K8CXK5Q32L)
Language	English
Publishing date	2020-07-29
Publishing country	Switzerland
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2516098-9
ISSN	1999-4915 ; 1999-4915
ISSN (online)	1999-4915
ISSN	1999-4915
DOI	10.3390/v12080821
Database	MEDical Literature Analysis and Retrieval System OnLINE

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