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Article ; Online: Roles of ESCRT Proteins ALIX and CHMP4A and Their Interplay with Interferon-Stimulated Gene 15 during Tick-Borne Flavivirus Infection.

Tran, Pham-Tue-Hung / Chiramel, Abhilash I / Johansson, Magnus / Melik, Wessam

2021 Volume 96, Issue 3, Page(s) e0162421

Abstract: Flaviviruses are usually transmitted to humans via mosquito or tick bites. During infection, virus replication and assembly, whose cellular sites are relatively close, are controlled by virus proteins and a diverse range of host proteins. By siRNA- ... ...

Abstract	Flaviviruses are usually transmitted to humans via mosquito or tick bites. During infection, virus replication and assembly, whose cellular sites are relatively close, are controlled by virus proteins and a diverse range of host proteins. By siRNA-mediated gene silencing, we showed that ALIX and CHMP4A, two members of the host endosomal sorting complex required for transport (ESCRT) protein machinery, are required during flavivirus infection. Using cell lines expressing subgenomic replicons and replicon virus-like particles, we demonstrated specific roles for ALIX and CHMP4A in viral replication and assembly, respectively. Employing biochemical and imaging methodology, we showed that the ESCRT proteins are recruited by a putative specific late (L) domain motif LYXLA within the NS3 protein of tick-borne flaviviruses. Furthermore, to counteract the recruitment of ESCRT proteins, the host cells may elicit defense mechanisms. We found that ectopic expression of the interferon-stimulated gene 15 (ISG15) or the E3 ISG15-protein ligase (HERC5) reduced virus replication by suppressing the positive effects of ALIX and CHMP4A. Collectively, these results have provided new insights into flavivirus-host cell interactions that function as checkpoints, including the NS3 and the ESCRT proteins, the ISG15 and the ESCRT proteins, at essential stages of the virus life cycle.
MeSH term(s)	Animals ; Calcium-Binding Proteins/metabolism ; Cell Cycle Proteins/metabolism ; Cell Line ; Cells, Cultured ; Cytokines/metabolism ; Endosomal Sorting Complexes Required for Transport/metabolism ; Flavivirus/physiology ; Flavivirus Infections/metabolism ; Flavivirus Infections/transmission ; Flavivirus Infections/virology ; Host-Pathogen Interactions ; Humans ; Models, Biological ; Proteolysis ; Ticks/virology ; Ubiquitins/metabolism ; Virus Replication
Chemical Substances	CHMP4A protein, human ; Calcium-Binding Proteins ; Cell Cycle Proteins ; Cytokines ; Endosomal Sorting Complexes Required for Transport ; PDCD6IP protein, human ; Ubiquitins ; ISG15 protein, human (60267-61-0)
Language	English
Publishing date	2021-12-01
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80174-4
ISSN	1098-5514 ; 0022-538X
ISSN (online)	1098-5514
ISSN	0022-538X
DOI	10.1128/JVI.01624-21
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Article ; Online: Role of autophagy in Zika virus infection and pathogenesis.

Chiramel, Abhilash I / Best, Sonja M

Virus research

2017 Volume 254, Page(s) 34–40

Abstract: Autophagy is an evolutionarily conserved cellular pathway that culminates in lysosomal degradation of selected substrates. Autophagy can serve dual roles in virus infection with either pro- or antiviral functions depending on the virus and the stage of ... ...

Abstract	Autophagy is an evolutionarily conserved cellular pathway that culminates in lysosomal degradation of selected substrates. Autophagy can serve dual roles in virus infection with either pro- or antiviral functions depending on the virus and the stage of the viral replication cycle. Recent studies have suggested a role for autophagy in Zika virus (ZIKV) replication by demonstrating the accumulation of autophagic vesicles following ZIKV infection in both in vitro and in vivo models. In human fetal neural stem cells, ZIKV inhibits Akt-mTOR signaling to induce autophagy, increase virus replication and impede neurogenesis. However, autophagy also has the potential to limit ZIKV replication, with separate studies demonstrating antiviral roles for autophagy at the maternal-placental-fetal interface, and more specifically, at the endoplasmic reticulum where virus replication is established in an infected cell. Interestingly, ZIKV (and related flaviviruses) has evolved specific mechanisms to overcome autophagy at the ER, thus demonstrating important roles for these autophagic pathways in virus replication and host response. This review summarizes the known roles of autophagy in ZIKV replication and how they might influence virus tissue tropism and disease.
MeSH term(s)	Animals ; Autophagy/physiology ; Female ; Humans ; Models, Biological ; Neurogenesis ; Pregnancy ; Viral Proteins/metabolism ; Virus Replication ; Zika Virus/physiology ; Zika Virus Infection/physiopathology ; Zika Virus Infection/virology
Chemical Substances	Viral Proteins
Language	English
Publishing date	2017-09-09
Publishing country	Netherlands
Document type	Journal Article ; Research Support, N.I.H., Intramural ; Review
ZDB-ID	605780-9
ISSN	1872-7492 ; 0168-1702
ISSN (online)	1872-7492
ISSN	0168-1702
DOI	10.1016/j.virusres.2017.09.006
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Article: Role of Autophagy in Zika Virus Infection and Pathogenesis

Chiramel, Abhilash I / Best, Sonja M

Virus research. 2017,

2017

Abstract	Autophagy is an evolutionarily conserved cellular pathway that culminates in lysosomal degradation of selected substrates. Autophagy can serve dual roles in virus infection with either pro- or antiviral functions depending on the virus and the stage of the viral replication cycle. Recent studies have suggested a role for autophagy in Zika virus (ZIKV) replication by demonstrating the accumulation of autophagic vesicles following ZIKV infection in both in vitro and in vivo models. In human fetal neural stem cells, ZIKV inhibits Akt-mTOR signaling to induce autophagy, increase virus replication and impede neurogenesis. However, autophagy also has the potential to limit ZIKV replication, with separate studies demonstrating antiviral roles for autophagy at the maternal-placental-fetal interface, and more specifically, at the endoplasmic reticulum where virus replication is established in an infected cell. Interestingly, ZIKV (and related flaviviruses) has evolved specific mechanisms to overcome autophagy at the ER, thus demonstrating important roles for these autophagic pathways in virus replication and host response. This review summarizes the known roles of autophagy in ZIKV replication and how they might influence virus tissue tropism and disease.
Keywords	Zika virus ; autophagy ; endoplasmic reticulum ; humans ; models ; neurogenesis ; pathogenesis ; stem cells ; tissue tropism ; virus replication ; viruses
Language	English
Publishing place	Elsevier B.V.
Document type	Article
Note	Pre-press version
ZDB-ID	605780-9
ISSN	1872-7492 ; 0168-1702
ISSN (online)	1872-7492
ISSN	0168-1702
DOI	10.1016/j.virusres.2017.09.006
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: The liver X receptor agonist LXR 623 restricts flavivirus replication.

Mlera, Luwanika / Offerdahl, Danielle K / Dorward, David W / Carmody, Aaron / Chiramel, Abhilash I / Best, Sonja M / Bloom, Marshall E

Emerging microbes & infections

2021 Volume 10, Issue 1, Page(s) 1378–1389

Abstract: The vector-borne flaviviruses (VBFVs) are well known for causing great misery and death in humans worldwide. The VBFVs include those transmitted by mosquitos, such as Zika virus (ZIKV), dengue virus; and those transmitted by ticks including the tick- ... ...

Abstract	The vector-borne flaviviruses (VBFVs) are well known for causing great misery and death in humans worldwide. The VBFVs include those transmitted by mosquitos, such as Zika virus (ZIKV), dengue virus; and those transmitted by ticks including the tick-borne flavivirus serocomplex and Powassan virus (POWV). Two of our recent reports showed that intracranial POWV infection in the reservoir host,
MeSH term(s)	Antiviral Agents/pharmacology ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cytokines/genetics ; Cytokines/metabolism ; Cytopathogenic Effect, Viral/drug effects ; Cytoplasmic Vesicles/drug effects ; Cytoplasmic Vesicles/metabolism ; Encephalitis Viruses, Tick-Borne/drug effects ; Encephalitis Viruses, Tick-Borne/physiology ; Endoplasmic Reticulum/drug effects ; Endoplasmic Reticulum/metabolism ; Humans ; Indazoles/pharmacology ; Liver X Receptors/agonists ; Liver X Receptors/metabolism ; Virus Replication/drug effects ; Zika Virus/drug effects ; Zika Virus/physiology
Chemical Substances	2-(2-chloro-4-fluorobenzyl)-3-(4-fluorophenyl)-7-(trifluoromethyl)-2H-indazole ; Antiviral Agents ; Cytokines ; Indazoles ; Liver X Receptors
Language	English
Publishing date	2021-06-20
Publishing country	United States
Document type	Journal Article
ZDB-ID	2681359-2
ISSN	2222-1751 ; 2222-1751
ISSN (online)	2222-1751
ISSN	2222-1751
DOI	10.1080/22221751.2021.1947749
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Article: Disruption of the Golgi Apparatus and Contribution of the Endoplasmic Reticulum to the SARS-CoV-2 Replication Complex

Hackstadt, Ted / Chiramel, Abhilash I. / Hoyt, Forrest H. / Williamson, Brandi N. / Dooley, Cheryl A. / Beare, Paul A. / de Wit, Emmie / Best, Sonja M. / Fischer, Elizabeth R.

Viruses. 2021 Sept. 09, v. 13, no. 9

2021

Abstract: A variety of immunolabeling procedures for both light and electron microscopy were used to examine the cellular origins of the host membranes supporting the SARS-CoV-2 replication complex. The endoplasmic reticulum has long been implicated as a source of ...

Abstract	A variety of immunolabeling procedures for both light and electron microscopy were used to examine the cellular origins of the host membranes supporting the SARS-CoV-2 replication complex. The endoplasmic reticulum has long been implicated as a source of membrane for the coronavirus replication organelle. Using dsRNA as a marker for sites of viral RNA synthesis, we provide additional evidence supporting ER as a prominent source of membrane. In addition, we observed a rapid fragmentation of the Golgi apparatus which is visible by 6 h and complete by 12 h post-infection. Golgi derived lipid appears to be incorporated into the replication organelle although protein markers are dispersed throughout the infected cell. The mechanism of Golgi disruption is undefined, but chemical disruption of the Golgi apparatus by brefeldin A is inhibitory to viral replication. A search for an individual SARS-CoV-2 protein responsible for this activity identified at least five viral proteins, M, S, E, Orf6, and nsp3, that induced Golgi fragmentation when expressed in eukaryotic cells. Each of these proteins, as well as nsp4, also caused visible changes to ER structure as shown by correlative light and electron microscopy (CLEM). Collectively, these results imply that specific disruption of the Golgi apparatus is a critical component of coronavirus replication.
Keywords	Golgi apparatus ; Severe acute respiratory syndrome coronavirus 2 ; brefeldin A ; electron microscopy ; endoplasmic reticulum ; lipids ; virus replication
Language	English
Dates of publication	2021-0909
Publishing place	Multidisciplinary Digital Publishing Institute
Document type	Article
ZDB-ID	2516098-9
ISSN	1999-4915
ISSN	1999-4915
DOI	10.3390/v13091798
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Article ; Online: Rapalogs downmodulate intrinsic immunity and promote cell entry of SARS-CoV-2.

Shi, Guoli / Chiramel, Abhilash I / Li, Tiansheng / Lai, Kin Kui / Kenney, Adam D / Zani, Ashley / Eddy, Adrian C / Majdoul, Saliha / Zhang, Lizhi / Dempsey, Tirhas / Beare, Paul A / Kar, Swagata / Yewdell, Jonathan W / Best, Sonja M / Yount, Jacob S / Compton, Alex A

The Journal of clinical investigation

2022 Volume 132, Issue 24

Abstract: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in immunocompromised individuals is associated with prolonged virus shedding and evolution of viral variants. Rapamycin and its analogs (rapalogs, including everolimus, temsirolimus, ... ...

Abstract	Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in immunocompromised individuals is associated with prolonged virus shedding and evolution of viral variants. Rapamycin and its analogs (rapalogs, including everolimus, temsirolimus, and ridaforolimus) are FDA approved as mTOR inhibitors for the treatment of human diseases, including cancer and autoimmunity. Rapalog use is commonly associated with an increased susceptibility to infection, which has been traditionally explained by impaired adaptive immunity. Here, we show that exposure to rapalogs increased susceptibility to SARS-CoV-2 infection in tissue culture and in immunologically naive rodents by antagonizing the cell-intrinsic immune response. We identified 1 rapalog (ridaforolimus) that was less potent in this regard and demonstrated that rapalogs promote spike-mediated entry into cells, by triggering the degradation of the antiviral proteins IFITM2 and IFITM3 via an endolysosomal remodeling program called microautophagy. Rapalogs that increased virus entry inhibited mTOR-mediated phosphorylation of the transcription factor TFEB, which facilitated its nuclear translocation and triggered microautophagy. In rodent models of infection, injection of rapamycin prior to and after virus exposure resulted in elevated SARS-CoV-2 replication and exacerbated viral disease, while ridaforolimus had milder effects. Overall, our findings indicate that preexisting use of certain rapalogs may elevate host susceptibility to SARS-CoV-2 infection and disease by activating lysosome-mediated suppression of intrinsic immunity.
MeSH term(s)	Humans ; SARS-CoV-2 ; MTOR Inhibitors ; Virus Internalization ; COVID-19 ; Sirolimus/pharmacology ; Immunity, Innate ; Membrane Proteins ; RNA-Binding Proteins
Chemical Substances	MTOR Inhibitors ; ridaforolimus (48Z35KB15K) ; Sirolimus (W36ZG6FT64) ; IFITM2 protein, human ; Membrane Proteins ; IFITM3 protein, human ; RNA-Binding Proteins
Language	English
Publishing date	2022-12-15
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, N.I.H., Intramural
ZDB-ID	3067-3
ISSN	1558-8238 ; 0021-9738
ISSN (online)	1558-8238
ISSN	0021-9738
DOI	10.1172/JCI160766
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Article: Rapalogs downmodulate intrinsic immunity and promote cell entry of SARS-CoV-2.

Shi, Guoli / Chiramel, Abhilash I / Li, Tiansheng / Lai, Kin Kui / Kenney, Adam D / Zani, Ashley / Eddy, Adrian / Majdoul, Saliha / Zhang, Lizhi / Dempsey, Tirhas / Beare, Paul A / Kar, Swagata / Yewdell, Jonathan W / Best, Sonja M / Yount, Jacob S / Compton, Alex A

bioRxiv : the preprint server for biology

2022

Abstract: SARS-CoV-2 infection in immunocompromised individuals is associated with prolonged virus shedding and evolution of viral variants. Rapamycin and its analogs (rapalogs, including everolimus, temsirolimus, and ridaforolimus) are FDA-approved as mTOR ... ...

Abstract	SARS-CoV-2 infection in immunocompromised individuals is associated with prolonged virus shedding and evolution of viral variants. Rapamycin and its analogs (rapalogs, including everolimus, temsirolimus, and ridaforolimus) are FDA-approved as mTOR inhibitors for the treatment of human diseases, including cancer and autoimmunity. Rapalog use is commonly associated with increased susceptibility to infection, which has been traditionally explained by impaired adaptive immunity. Here, we show that exposure to rapalogs increases susceptibility to SARS-CoV-2 infection in tissue culture and in immunologically naive rodents by antagonizing the cell-intrinsic immune response. By identifying one rapalog (ridaforolimus) that is less potent in this regard, we demonstrate that rapalogs promote Spike-mediated entry into cells by triggering the degradation of antiviral proteins IFITM2 and IFITM3 via an endolysosomal remodeling program called microautophagy. Rapalogs that increase virus entry inhibit the mTOR-mediated phosphorylation of the transcription factor TFEB, which facilitates its nuclear translocation and triggers microautophagy. In rodent models of infection, injection of rapamycin prior to and after virus exposure resulted in elevated SARS-CoV-2 replication and exacerbated viral disease, while ridaforolimus had milder effects. Overall, our findings indicate that preexisting use of certain rapalogs may elevate host susceptibility to SARS-CoV-2 infection and disease by activating lysosome-mediated suppression of intrinsic immunity.
Language	English
Publishing date	2022-08-30
Publishing country	United States
Document type	Preprint
DOI	10.1101/2021.04.15.440067
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Article: Divergent roles of autophagy in virus infection.

Chiramel, Abhilash I / Brady, Nathan R / Bartenschlager, Ralf

Cells

2013 Volume 2, Issue 1, Page(s) 83–104

Abstract: Viruses have played an important role in human evolution and have evolved diverse strategies to co-exist with their hosts. As obligate intracellular pathogens, viruses exploit and manipulate different host cell processes, including cellular trafficking, ... ...

Abstract	Viruses have played an important role in human evolution and have evolved diverse strategies to co-exist with their hosts. As obligate intracellular pathogens, viruses exploit and manipulate different host cell processes, including cellular trafficking, metabolism and immunity-related functions, for their own survival. In this article, we review evidence for how autophagy, a highly conserved cellular degradative pathway, serves either as an antiviral defense mechanism or, alternatively, as a pro-viral process during virus infection. Furthermore, we highlight recent reports concerning the role of selective autophagy in virus infection and how viruses manipulate autophagy to evade lysosomal capture and degradation.
Keywords	covid19
Language	English
Publishing date	2013-01-25
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2661518-6
ISSN	2073-4409
ISSN	2073-4409
DOI	10.3390/cells2010083
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Article ; Online: Genome-Wide CRISPR Screen Identifies RACK1 as a Critical Host Factor for Flavivirus Replication.

Shue, Byron / Chiramel, Abhilash I / Cerikan, Berati / To, Thu-Hien / Frölich, Sonja / Pederson, Stephen M / Kirby, Emily N / Eyre, Nicholas S / Bartenschlager, Ralf F W / Best, Sonja M / Beard, Michael R

Journal of virology

2021 Volume 95, Issue 24, Page(s) e0059621

Abstract: Cellular factors have important roles in all facets of the flavivirus replication cycle. Deciphering viral-host protein interactions is essential for understanding the flavivirus life cycle as well as development of effective antiviral strategies. To ... ...

Abstract	Cellular factors have important roles in all facets of the flavivirus replication cycle. Deciphering viral-host protein interactions is essential for understanding the flavivirus life cycle as well as development of effective antiviral strategies. To uncover novel host factors that are co-opted by multiple flaviviruses, a CRISPR/Cas9 genome wide knockout (KO) screen was employed to identify genes required for replication of Zika virus (ZIKV). Receptor for Activated Protein C Kinase 1 (RACK1) was identified as a novel host factor required for ZIKV replication, which was confirmed via complementary experiments. Depletion of RACK1 via siRNA demonstrated that RACK1 is important for replication of a wide range of mosquito- and tick-borne flaviviruses, including West Nile Virus (WNV), Dengue Virus (DENV), Powassan Virus (POWV) and Langat Virus (LGTV) as well as the coronavirus SARS-CoV-2, but not for YFV, EBOV, VSV or HSV. Notably, flavivirus replication was only abrogated when RACK1 expression was dampened prior to infection. Utilising a non-replicative flavivirus model, we show altered morphology of viral replication factories and reduced formation of vesicle packets (VPs) in cells lacking RACK1 expression. In addition, RACK1 interacted with NS1 protein from multiple flaviviruses; a key protein for replication complex formation. Overall, these findings reveal RACK1's crucial role to the biogenesis of pan-flavivirus replication organelles.
MeSH term(s)	A549 Cells ; Aedes ; Animals ; COVID-19 ; CRISPR-Cas Systems ; Chlorocebus aethiops ; Culicidae ; Dengue Virus/genetics ; Flavivirus/genetics ; Genome-Wide Association Study ; HEK293 Cells ; Host-Pathogen Interactions/genetics ; Humans ; Neoplasm Proteins/genetics ; RNA, Small Interfering/metabolism ; RNA, Viral/metabolism ; Receptors for Activated C Kinase/genetics ; SARS-CoV-2 ; Vero Cells ; Virus Replication ; West Nile virus/genetics ; Zika Virus/genetics ; Zika Virus Infection/virology
Chemical Substances	Neoplasm Proteins ; RACK1 protein, human ; RNA, Small Interfering ; RNA, Viral ; Receptors for Activated C Kinase
Language	English
Publishing date	2021-09-29
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80174-4
ISSN	1098-5514 ; 0022-538X
ISSN (online)	1098-5514
ISSN	0022-538X
DOI	10.1128/JVI.00596-21
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Article ; Online: Disruption of the Golgi Apparatus and Contribution of the Endoplasmic Reticulum to the SARS-CoV-2 Replication Complex.

Hackstadt, Ted / Chiramel, Abhilash I / Hoyt, Forrest H / Williamson, Brandi N / Dooley, Cheryl A / Beare, Paul A / de Wit, Emmie / Best, Sonja M / Fischer, Elizabeth R

Viruses

2021 Volume 13, Issue 9

Abstract	A variety of immunolabeling procedures for both light and electron microscopy were used to examine the cellular origins of the host membranes supporting the SARS-CoV-2 replication complex. The endoplasmic reticulum has long been implicated as a source of membrane for the coronavirus replication organelle. Using dsRNA as a marker for sites of viral RNA synthesis, we provide additional evidence supporting ER as a prominent source of membrane. In addition, we observed a rapid fragmentation of the Golgi apparatus which is visible by 6 h and complete by 12 h post-infection. Golgi derived lipid appears to be incorporated into the replication organelle although protein markers are dispersed throughout the infected cell. The mechanism of Golgi disruption is undefined, but chemical disruption of the Golgi apparatus by brefeldin A is inhibitory to viral replication. A search for an individual SARS-CoV-2 protein responsible for this activity identified at least five viral proteins, M, S, E, Orf6, and nsp3, that induced Golgi fragmentation when expressed in eukaryotic cells. Each of these proteins, as well as nsp4, also caused visible changes to ER structure as shown by correlative light and electron microscopy (CLEM). Collectively, these results imply that specific disruption of the Golgi apparatus is a critical component of coronavirus replication.
MeSH term(s)	Animals ; Chlorocebus aethiops ; Coronavirus M Proteins/physiology ; Coronavirus M Proteins/ultrastructure ; Endoplasmic Reticulum/ultrastructure ; Endoplasmic Reticulum/virology ; Golgi Apparatus/ultrastructure ; Golgi Apparatus/virology ; Humans ; Intracellular Membranes/ultrastructure ; Intracellular Membranes/virology ; Microscopy, Electron ; SARS-CoV-2/physiology ; SARS-CoV-2/ultrastructure ; Vero Cells ; Viral Structural Proteins/physiology ; Viral Structural Proteins/ultrastructure ; Virus Replication
Chemical Substances	Coronavirus M Proteins ; M protein, SARS-CoV ; Viral Structural Proteins
Language	English
Publishing date	2021-09-09
Publishing country	Switzerland
Document type	Journal Article ; Research Support, N.I.H., Intramural
ZDB-ID	2516098-9
ISSN	1999-4915 ; 1999-4915
ISSN (online)	1999-4915
ISSN	1999-4915
DOI	10.3390/v13091798
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