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Article: PARP14 is pro- and anti-viral host factor that promotes IFN production and affects the replication of multiple viruses.

Parthasarathy, Srivatsan / Saenjamsai, Pradtahna / Hao, Hongping / Ferkul, Anna / Pfannenstiel, Jessica J / Suder, Ellen L / Bejan, Daniel S / Chen, Yating / Schwarting, Nancy / Aikawa, Masanori / Muhlberger, Elke / Orozco, Robin C / Sullivan, Christopher S / Cohen, Michael S / Davido, David J / Hume, Adam J / Fehr, Anthony R

bioRxiv : the preprint server for biology

2024

Abstract: PARP14 is a 203 kDa multi-domain protein that is primarily known as an ADP-ribosyltransferase, and is involved in a variety of cellular functions including DNA damage, microglial activation, inflammation, and cancer progression. In addition, PARP14 is ... ...

Abstract	PARP14 is a 203 kDa multi-domain protein that is primarily known as an ADP-ribosyltransferase, and is involved in a variety of cellular functions including DNA damage, microglial activation, inflammation, and cancer progression. In addition, PARP14 is upregulated by interferon (IFN), indicating a role in the antiviral response. Furthermore, PARP14 has evolved under positive selection, again indicating that it is involved in host-pathogen conflict. We found that PARP14 is required for increased IFN-I production in response to coronavirus infection lacking ADP-ribosylhydrolase (ARH) activity and poly(I:C), however, whether it has direct antiviral function remains unclear. Here we demonstrate that the catalytic activity of PARP14 enhances IFN-I and IFN-III responses and restricts ARH-deficient murine hepatitis virus (MHV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replication. To determine if PARP14's antiviral functions extended beyond CoVs, we tested the ability of herpes simplex virus 1 (HSV-1) and several negative-sense RNA viruses, including vesicular stomatitis virus (VSV), Ebola virus (EBOV), and Nipah virus (NiV), to infect A549 PARP14 knockout (KO) cells. HSV-1 had increased replication in PARP14 KO cells, indicating that PARP14 restricts HSV-1 replication. In contrast, PARP14 was critical for the efficient infection of VSV, EBOV, and NiV, with EBOV infectivity at less than 1% of WT cells. A PARP14 active site inhibitor had no impact on HSV-1 or EBOV infection, indicating that its effect on these viruses was independent of its catalytic activity. These data demonstrate that PARP14 promotes IFN production and has both pro- and anti-viral functions targeting multiple viruses.
Language	English
Publishing date	2024-04-26
Publishing country	United States
Document type	Preprint
DOI	10.1101/2024.04.26.591186
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: CD169-mediated restrictive SARS-CoV-2 infection of macrophages induces pro-inflammatory responses.

Jalloh, Sallieu / Olejnik, Judith / Berrigan, Jacob / Nisa, Annuurun / Suder, Ellen L / Akiyama, Hisashi / Lei, Maohua / Tyagi, Sanjay / Bushkin, Yuri / Mühlberger, Elke / Gummuluru, Suryaram

bioRxiv : the preprint server for biology

2022

Abstract: Exacerbated and persistent innate immune response marked by pro-inflammatory cytokine expression is thought to be a major driver of chronic COVID-19 pathology. Although macrophages are not the primary target cells of SARS-CoV-2 infection in humans, viral ...

Abstract	Exacerbated and persistent innate immune response marked by pro-inflammatory cytokine expression is thought to be a major driver of chronic COVID-19 pathology. Although macrophages are not the primary target cells of SARS-CoV-2 infection in humans, viral RNA and antigens in activated monocytes and macrophages have been detected in post-mortem samples, and dysfunctional monocytes and macrophages have been hypothesized to contribute to a protracted hyper-inflammatory state in COVID-19 patients. In this study, we demonstrate that CD169, a myeloid cell specific I-type lectin, facilitated ACE2-independent SARS-CoV-2 fusion and entry in macrophages. CD169- mediated SARS-CoV-2 entry in macrophages resulted in expression of viral genomic and sub-genomic (sg) RNAs with minimal viral protein expression and no infectious viral particle release, suggesting a post-entry restriction of the SARS-CoV-2 replication cycle. Intriguingly this post-entry replication block was alleviated by exogenous ACE2 expression in macrophages. Restricted expression of viral gRNA and sgRNA in CD169 Author summary: Over-exuberant production of pro-inflammatory cytokine expression by macrophages has been hypothesized to contribute to severity of COVID-19 disease. Molecular mechanisms that contribute to macrophage-intrinsic immune activation during SARS- CoV-2 infection are not fully understood. Here we show that CD169, a macrophage- specific sialic-acid binding lectin, facilitates abortive SARS-CoV-2 infection of macrophages that results in innate immune sensing of viral replication intermediates and production of proinflammatory responses. We identify an ACE2-independent, CD169- mediated endosomal viral entry mechanism that results in cytoplasmic delivery of viral capsids and initiation of virus replication, but absence of infectious viral production. Restricted viral replication in CD169
Language	English
Publishing date	2022-03-30
Publishing country	United States
Document type	Preprint
DOI	10.1101/2022.03.29.486190
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Article ; Online: CD169-mediated restrictive SARS-CoV-2 infection of macrophages induces pro-inflammatory responses.

Jalloh, Sallieu / Olejnik, Judith / Berrigan, Jacob / Nisa, Annuurun / Suder, Ellen L / Akiyama, Hisashi / Lei, Maohua / Ramaswamy, Sita / Tyagi, Sanjay / Bushkin, Yuri / Mühlberger, Elke / Gummuluru, Suryaram

PLoS pathogens

2022 Volume 18, Issue 10, Page(s) e1010479

Abstract	Exacerbated and persistent innate immune response marked by pro-inflammatory cytokine expression is thought to be a major driver of chronic COVID-19 pathology. Although macrophages are not the primary target cells of SARS-CoV-2 infection in humans, viral RNA and antigens in activated monocytes and macrophages have been detected in post-mortem samples, and dysfunctional monocytes and macrophages have been hypothesized to contribute to a protracted hyper-inflammatory state in COVID-19 patients. In this study, we demonstrate that CD169, a myeloid cell specific I-type lectin, facilitated ACE2-independent SARS-CoV-2 fusion and entry in macrophages. CD169-mediated SARS-CoV-2 entry in macrophages resulted in expression of viral genomic and subgenomic RNAs with minimal viral protein expression and no infectious viral particle release, suggesting a post-entry restriction of the SARS-CoV-2 replication cycle. Intriguingly this post-entry replication block was alleviated by exogenous ACE2 expression in macrophages. Restricted expression of viral genomic and subgenomic RNA in CD169+ macrophages elicited a pro-inflammatory cytokine expression (TNFα, IL-6 and IL-1β) in a RIG-I, MDA-5 and MAVS-dependent manner, which was suppressed by remdesivir treatment. These findings suggest that de novo expression of SARS-CoV-2 RNA in macrophages contributes to the pro-inflammatory cytokine signature and that blocking CD169-mediated ACE2 independent infection and subsequent activation of macrophages by viral RNA might alleviate COVID-19-associated hyperinflammatory response.
MeSH term(s)	Humans ; Angiotensin-Converting Enzyme 2/genetics ; COVID-19 ; Cytokines/metabolism ; Macrophages ; RNA, Viral/metabolism ; SARS-CoV-2
Chemical Substances	Angiotensin-Converting Enzyme 2 (EC 3.4.17.23) ; Cytokines ; RNA, Viral ; SIGLEC1 protein, human
Language	English
Publishing date	2022-10-24
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	2205412-1
ISSN	1553-7374 ; 1553-7374
ISSN (online)	1553-7374
ISSN	1553-7374
DOI	10.1371/journal.ppat.1010479
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: Reconstructed signaling and regulatory networks identify potential drugs for SARS-CoV-2 infection.

Ding, Jun / Lugo-Martinez, Jose / Yuan, Ye / Huang, Jessie / Hume, Adam J / Suder, Ellen L / Mühlberger, Elke / Kotton, Darrell N / Bar-Joseph, Ziv

bioRxiv : the preprint server for biology

2021

Abstract: Several molecular datasets have been recently compiled to characterize the activity of SARS-CoV-2 within human cells. Here we extend computational methods to integrate several different types of sequence, functional and interaction data to reconstruct ... ...

Abstract	Several molecular datasets have been recently compiled to characterize the activity of SARS-CoV-2 within human cells. Here we extend computational methods to integrate several different types of sequence, functional and interaction data to reconstruct networks and pathways activated by the virus in host cells. We identify key proteins in these networks and further intersect them with genes differentially expressed at conditions that are known to impact viral activity. Several of the top ranked genes do not directly interact with virus proteins. We experimentally tested treatments for a number of the predicted targets. We show that blocking one of the predicted indirect targets significantly reduces viral loads in stem cell-derived alveolar epithelial type II cells (iAT2s).
Keywords	covid19
Language	English
Publishing date	2021-12-09
Publishing country	United States
Document type	Preprint
DOI	10.1101/2020.06.01.127589
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Article ; Online: Isolation and genome characterization of Lloviu virus from Italian Schreibers's bats.

Scientific reports

2023 Volume 13, Issue 1, Page(s) 11310

Abstract: Lloviu cuevavirus (LLOV) was the first identified member of Filoviridae family outside the Ebola and Marburgvirus genera. A massive die-off of Schreibers's bats (Miniopterus schreibersii) in the Iberian Peninsula in 2002 led to its initial discovery. ... ...

Abstract	Lloviu cuevavirus (LLOV) was the first identified member of Filoviridae family outside the Ebola and Marburgvirus genera. A massive die-off of Schreibers's bats (Miniopterus schreibersii) in the Iberian Peninsula in 2002 led to its initial discovery. Recent studies with recombinant and wild-type LLOV isolates confirmed the zoonotic nature of the virus in vitro. We examined bat samples from Italy for the presence of LLOV in an area outside of the currently known distribution range of the virus. We detected one positive sample from 2020, sequenced the complete coding region of the viral genome and established an infectious isolate of the virus. In addition, we performed the first comprehensive evolutionary analysis of the virus, using the Spanish, Hungarian and the Italian sequences. The most important achievement of this study is the establishment of an additional infectious LLOV isolate from a bat sample using the SuBK12-08 cells, demonstrating that this cell line is highly susceptible to LLOV infection and confirming the previous observation that these bats are effective hosts of the virus in nature. This result further strengthens the role of bats as the natural hosts for zoonotic filoviruses.
MeSH term(s)	Animals ; Chiroptera ; Filoviridae/genetics ; Marburgvirus ; Cell Line ; Italy ; Phylogeny
Language	English
Publishing date	2023-07-13
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-023-38364-7
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: CD169-mediated restrictive SARS-CoV-2 infection of macrophages induces pro-inflammatory responses

Jalloh, Sallieu / Olejnik, Judith / Berrigan, Jacob / Nisa, Annuurun / Suder, Ellen L / Akiyama, Hisashi / Lei, Maohua / Tyagi, Sanjay / Bushkin, Yuri / Muhlberger, Elke / Gummuluru, Suryaram

bioRxiv

Abstract	Exacerbated and persistent innate immune response marked by pro-inflammatory cytokine expression is thought to be a major driver of chronic COVID-19 pathology. Although macrophages are not the primary target cells of SARS-CoV-2 infection in humans, viral RNA and antigens in activated monocytes and macrophages have been detected in post-mortem samples, and dysfunctional monocytes and macrophages have been hypothesized to contribute to a protracted hyper-inflammatory state in COVID-19 patients. In this study, we demonstrate that CD169, a myeloid cell specific I-type lectin, facilitated ACE2-independent SARS-CoV-2 fusion and entry in macrophages. CD169-mediated SARS-CoV-2 entry in macrophages resulted in expression of viral genomic and sub-genomic (sg) RNAs with minimal viral protein expression and no infectious viral particle release, suggesting a post-entry restriction of the SARS-CoV-2 replication cycle. Intriguingly this post-entry replication block was alleviated by exogenous ACE2 expression in macrophages. Restricted expression of viral gRNA and sgRNA in CD169 + macrophages elicited a pro-inflammatory cytokine expression (TNFα, IL-6 and IL-1β) in a RIG-I, MDA-5 and MAVS-dependent manner, which was suppressed by remdesivir pre-treatment. These findings suggest that de novo expression of SARS-CoV-2 RNA in macrophages contributes to the pro-inflammatory cytokine signature and that blocking CD169-mediated ACE2 independent infection and subsequent activation of macrophages by viral RNA might alleviate COVID-19-associated hyperinflammatory response.
Keywords	covid19
Language	English
Publishing date	2022-03-30
Publisher	Cold Spring Harbor Laboratory
Document type	Article ; Online
DOI	10.1101/2022.03.29.486190
Database	COVID19

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Article: CD209L/L-SIGN and CD209/DC-SIGN act as receptors for SARS-CoV-2.

Amraei, Razie / Yin, Wenqing / Napoleon, Marc A / Suder, Ellen L / Berrigan, Jacob / Zhao, Qing / Olejnik, Judith / Chandler, Kevin Brown / Xia, Chaoshuang / Feldman, Jared / Hauser, Blake M / Caradonna, Timothy M / Schmidt, Aaron G / Gummuluru, Suryaram / Muhlberger, Elke / Chitalia, Vipul / Costello, Catherine E / Rahimi, Nader

bioRxiv : the preprint server for biology

2021

Abstract: As the COVID-19 pandemic continues to spread, investigating the processes underlying the interactions between SARS-CoV-2 and its hosts is of high importance. Here, we report the identification of CD209L/L-SIGN and the related protein CD209/DC-SIGN as ... ...

Abstract	As the COVID-19 pandemic continues to spread, investigating the processes underlying the interactions between SARS-CoV-2 and its hosts is of high importance. Here, we report the identification of CD209L/L-SIGN and the related protein CD209/DC-SIGN as receptors capable of mediating SARS-CoV-2 entry into human cells. Immunofluorescence staining of human tissues revealed prominent expression of CD209L in the lung and kidney epithelium and endothelium. Multiple biochemical assays using a purified recombinant SARS-CoV-2 spike receptor binding domain (S-RBD) or S1 encompassing both NTB and RBD and ectopically expressed CD209L and CD209 revealed that CD209L and CD209 interact with S-RBD. CD209L contains two
Keywords	covid19
Language	English
Publishing date	2021-06-14
Publishing country	United States
Document type	Preprint
DOI	10.1101/2020.06.22.165803
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Article: CD209L/L-SIGN and CD209/DC-SIGN Act as Receptors for SARS-CoV-2.

Amraei, Razie / Yin, Wenqing / Napoleon, Marc A / Suder, Ellen L / Berrigan, Jacob / Zhao, Qing / Olejnik, Judith / Chandler, Kevin Brown / Xia, Chaoshuang / Feldman, Jared / Hauser, Blake M / Caradonna, Timothy M / Schmidt, Aaron G / Gummuluru, Suryaram / Mühlberger, Elke / Chitalia, Vipul / Costello, Catherine E / Rahimi, Nader

ACS central science

2021 Volume 7, Issue 7, Page(s) 1156–1165

Abstract	As the COVID-19 pandemic continues to spread, investigating the processes underlying the interactions between SARS-CoV-2 and its hosts is of high importance. Here, we report the identification of CD209L/L-SIGN and the related protein CD209/DC-SIGN as receptors capable of mediating SARS-CoV-2 entry into human cells. Immunofluorescence staining of human tissues revealed prominent expression of CD209L in the lung and kidney epithelia and endothelia. Multiple biochemical assays using a purified recombinant SARS-CoV-2 spike receptor-binding domain (S-RBD) or S1 encompassing both N termal domain and RBD and ectopically expressed CD209L and CD209 revealed that CD209L and CD209 interact with S-RBD. CD209L contains two
Language	English
Publishing date	2021-06-30
Publishing country	United States
Document type	Journal Article
ISSN	2374-7943
ISSN	2374-7943
DOI	10.1021/acscentsci.0c01537
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Ebola virus infection induces a delayed type I IFN response in bystander cells and the shutdown of key liver genes in human iPSC-derived hepatocytes.

Scoon, Whitney A / Mancio-Silva, Liliana / Suder, Ellen L / Villacorta-Martin, Carlos / Lindstrom-Vautrin, Jonathan / Bernbaum, John G / Mazur, Steve / Johnson, Reed F / Olejnik, Judith / Flores, Elizabeth Y / Mithal, Aditya / Wang, Feiya / Hume, Adam J / Kaserman, Joseph E / March-Riera, Sandra / Wilson, Andrew A / Bhatia, Sangeeta N / Mühlberger, Elke / Mostoslavsky, Gustavo

Stem cell reports

2022 Volume 17, Issue 10, Page(s) 2286–2302

Abstract: Liver damage and an exacerbated inflammatory response are hallmarks of Ebola virus (EBOV) infection. Little is known about the intrinsic response to infection in human hepatocytes and their contribution to inflammation. Here, we present an induced ... ...

Abstract	Liver damage and an exacerbated inflammatory response are hallmarks of Ebola virus (EBOV) infection. Little is known about the intrinsic response to infection in human hepatocytes and their contribution to inflammation. Here, we present an induced pluripotent stem cell (iPSC)-derived hepatocyte-like cell (HLC) platform to define the hepato-intrinsic response to EBOV infection. We used this platform to show robust EBOV infection, with characteristic ultrastructural changes and evidence for viral replication. Transcriptomics analysis revealed a delayed response with minimal early transcriptomic changes, followed by a general downregulation of hepatic function and upregulation of interferon signaling, providing a potential mechanism by which hepatocytes participate in disease severity and liver damage. Using RNA-fluorescence in situ hybridization (FISH), we showed that IFNB1 and CXCL10 were mainly expressed in non-infected bystander cells. We did not observe an inflammatory signature during infection. In conclusion, iPSC-HLCs are an immune competent platform to study responses to EBOV infection.
MeSH term(s)	Ebolavirus/physiology ; Hemorrhagic Fever, Ebola ; Hepatocytes ; Humans ; In Situ Hybridization, Fluorescence ; Induced Pluripotent Stem Cells ; Interferons ; Liver ; RNA
Chemical Substances	RNA (63231-63-0) ; Interferons (9008-11-1)
Language	English
Publishing date	2022-09-08
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	2720528-9
ISSN	2213-6711 ; 2213-6711
ISSN (online)	2213-6711
ISSN	2213-6711
DOI	10.1016/j.stemcr.2022.08.003
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Article ; Online: Recombinant Lloviu virus as a tool to study viral replication and host responses.

Hume, Adam J / Heiden, Baylee / Olejnik, Judith / Suder, Ellen L / Ross, Stephen / Scoon, Whitney A / Bullitt, Esther / Ericsson, Maria / White, Mitchell R / Turcinovic, Jacquelyn / Thao, Tran T N / Hekman, Ryan M / Kaserman, Joseph E / Huang, Jessie / Alysandratos, Konstantinos-Dionysios / Toth, Gabor E / Jakab, Ferenc / Kotton, Darrell N / Wilson, Andrew A /

Emili, Andrew / Thiel, Volker / Connor, John H / Kemenesi, Gabor / Cifuentes, Daniel / Mühlberger, Elke

PLoS pathogens

2022 Volume 18, Issue 2, Page(s) e1010268

Abstract: Next generation sequencing has revealed the presence of numerous RNA viruses in animal reservoir hosts, including many closely related to known human pathogens. Despite their zoonotic potential, most of these viruses remain understudied due to not yet ... ...

Abstract	Next generation sequencing has revealed the presence of numerous RNA viruses in animal reservoir hosts, including many closely related to known human pathogens. Despite their zoonotic potential, most of these viruses remain understudied due to not yet being cultured. While reverse genetic systems can facilitate virus rescue, this is often hindered by missing viral genome ends. A prime example is Lloviu virus (LLOV), an uncultured filovirus that is closely related to the highly pathogenic Ebola virus. Using minigenome systems, we complemented the missing LLOV genomic ends and identified cis-acting elements required for LLOV replication that were lacking in the published sequence. We leveraged these data to generate recombinant full-length LLOV clones and rescue infectious virus. Similar to other filoviruses, recombinant LLOV (rLLOV) forms filamentous virions and induces the formation of characteristic inclusions in the cytoplasm of the infected cells, as shown by electron microscopy. Known target cells of Ebola virus, including macrophages and hepatocytes, are permissive to rLLOV infection, suggesting that humans could be potential hosts. However, inflammatory responses in human macrophages, a hallmark of Ebola virus disease, are not induced by rLLOV. Additional tropism testing identified pneumocytes as capable of robust rLLOV and Ebola virus infection. We also used rLLOV to test antivirals targeting multiple facets of the replication cycle. Rescue of uncultured viruses of pathogenic concern represents a valuable tool in our arsenal for pandemic preparedness.
MeSH term(s)	Animals ; Cell Line ; Chlorocebus aethiops ; Ebolavirus/genetics ; Filoviridae/genetics ; Filoviridae Infections/virology ; Genetic Complementation Test ; Genome, Viral ; Hemorrhagic Fever, Ebola/virology ; Host Microbial Interactions ; Humans ; Inclusion Bodies/virology ; Induced Pluripotent Stem Cells/virology ; Macrophages/virology ; RNA, Viral ; Reverse Genetics ; Vero Cells ; Virion/genetics ; Virus Replication
Chemical Substances	RNA, Viral
Language	English
Publishing date	2022-02-04
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2205412-1
ISSN	1553-7374 ; 1553-7374
ISSN (online)	1553-7374
ISSN	1553-7374
DOI	10.1371/journal.ppat.1010268
Database	MEDical Literature Analysis and Retrieval System OnLINE

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