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Artikel ; Online: Lessons in self-defence: inhibition of virus entry by intrinsic immunity.

Majdoul, Saliha / Compton, Alex A

2021 Band 22, Heft 6, Seite(n) 339–352

Abstract: Virus entry, consisting of attachment to and penetration into the host target cell, is the first step of the virus life cycle and is a critical 'do or die' event that governs virus emergence in host populations. Most antiviral vaccines induce ... ...

Abstract	Virus entry, consisting of attachment to and penetration into the host target cell, is the first step of the virus life cycle and is a critical 'do or die' event that governs virus emergence in host populations. Most antiviral vaccines induce neutralizing antibodies that prevent virus entry into cells. However, while the prevention of virus invasion by humoral immunity is well appreciated, considerably less is known about the immune defences present within cells (known as intrinsic immunity) that interfere with virus entry. The interferon-induced transmembrane (IFITM) proteins, known for inhibiting fusion between viral and cellular membranes, were once the only factors known to restrict virus entry. However, the progressive development of genetic and pharmacological screening platforms and the onset of the COVID-19 pandemic have galvanized interest in how viruses infiltrate cells and how cells defend against it. Several host factors with antiviral potential are now implicated in the regulation of virus entry, including cholesterol 25-hydroxylase (CH25H), lymphocyte antigen 6E (LY6E), nuclear receptor co-activator protein 7 (NCOA7), interferon-γ-inducible lysosomal thiol reductase (GILT), CD74 and ARFGAP with dual pleckstrin homology domain-containing protein 2 (ADAP2). This Review summarizes what is known and what remains to be understood about the intrinsic factors that form the first line of defence against virus infection.
Mesh-Begriff(e)	Antiviral Agents ; COVID-19 ; Humans ; Interferons ; Membrane Proteins/metabolism ; Pandemics ; Virus Internalization
Chemische Substanzen	Antiviral Agents ; Membrane Proteins ; Interferons (9008-11-1)
Sprache	Englisch
Erscheinungsdatum	2021-10-13
Erscheinungsland	England
Dokumenttyp	Journal Article ; Review ; Research Support, N.I.H., Intramural
ZDB-ID	2062776-2
ISSN	1474-1741 ; 1474-1733
ISSN (online)	1474-1741
ISSN	1474-1733
DOI	10.1038/s41577-021-00626-8
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel ; Online: Restriction of Influenza A Virus by SERINC5.

Lai, Kin Kui / Munro, James B / Shi, Guoli / Majdoul, Saliha / Compton, Alex A / Rein, Alan

mBio

2022 Band 13, Heft 6, Seite(n) e0292322

Abstract: Serine incorporator 5 (Ser5), a transmembrane protein, has recently been identified as a host antiviral factor against human immunodeficiency virus (HIV)-1 and gammaretroviruses like murine leukemia viruses (MLVs). It is counteracted by HIV-1 Nef and MLV ...

Abstract	Serine incorporator 5 (Ser5), a transmembrane protein, has recently been identified as a host antiviral factor against human immunodeficiency virus (HIV)-1 and gammaretroviruses like murine leukemia viruses (MLVs). It is counteracted by HIV-1 Nef and MLV glycogag. We have investigated whether it has antiviral activity against influenza A virus (IAV), as well as retroviruses. Here, we demonstrated that Ser5 inhibited HIV-1-based pseudovirions bearing IAV hemagglutinin (HA); as expected, the Ser5 effect on this glycoprotein was antagonized by HIV-1 Nef protein. We found that Ser5 inhibited the virus-cell and cell-cell fusion of IAV, apparently by interacting with HA proteins. Most importantly, overexpressed and endogenous Ser5 inhibited infection by authentic IAV. Single-molecular fluorescent resonance energy transfer (smFRET) analysis further revealed that Ser5 both destabilized the pre-fusion conformation of IAV HA and inhibited the coiled-coil formation during membrane fusion. Ser5 is expressed in cultured small airway epithelial cells, as well as in immortal human cell lines. In summary, Ser5 is a host antiviral factor against IAV which acts by blocking HA-induced membrane fusion.
Mesh-Begriff(e)	Animals ; Mice ; Humans ; Influenza A virus ; Hemagglutinins ; Membrane Proteins/metabolism ; Leukemia Virus, Murine ; Cell Line
Chemische Substanzen	Hemagglutinins ; Membrane Proteins ; SERINC5 protein, human
Sprache	Englisch
Erscheinungsdatum	2022-11-21
Erscheinungsland	United States
Dokumenttyp	Journal Article
ZDB-ID	2557172-2
ISSN	2150-7511 ; 2161-2129
ISSN (online)	2150-7511
ISSN	2161-2129
DOI	10.1128/mbio.02923-22
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel ; Online: Homology-guided identification of a conserved motif linking the antiviral functions of IFITM3 to its oligomeric state.

Rahman, Kazi / Coomer, Charles A / Majdoul, Saliha / Ding, Selena Y / Padilla-Parra, Sergi / Compton, Alex A

eLife

2020 Band 9

Abstract: The interferon-inducible transmembrane (IFITM) proteins belong to the Dispanin/CD225 family and inhibit diverse virus infections. IFITM3 reduces membrane fusion between cells and virions through a poorly characterized mechanism. Mutation of proline-rich ... ...

Abstract	The interferon-inducible transmembrane (IFITM) proteins belong to the Dispanin/CD225 family and inhibit diverse virus infections. IFITM3 reduces membrane fusion between cells and virions through a poorly characterized mechanism. Mutation of proline-rich transmembrane protein 2 (PRRT2), a regulator of neurotransmitter release, at glycine-305 was previously linked to paroxysmal neurological disorders in humans. Here, we show that glycine-305 and the homologous site in IFITM3, glycine-95, drive protein oligomerization from within a GxxxG motif. Mutation of glycine-95 (and to a lesser extent, glycine-91) disrupted IFITM3 oligomerization and reduced its antiviral activity against Influenza A virus. An oligomerization-defective variant was used to reveal that IFITM3 promotes membrane rigidity in a glycine-95-dependent and amphipathic helix-dependent manner. Furthermore, a compound which counteracts virus inhibition by IFITM3, Amphotericin B, prevented the IFITM3-mediated rigidification of membranes. Overall, these data suggest that IFITM3 oligomers inhibit virus-cell fusion by promoting membrane rigidity.
Mesh-Begriff(e)	Amino Acid Motifs ; Cell Line ; HEK293 Cells ; Humans ; Influenza A virus/genetics ; Influenza A virus/physiology ; Influenza, Human/genetics ; Influenza, Human/immunology ; Influenza, Human/virology ; Membrane Proteins/chemistry ; Membrane Proteins/genetics ; Membrane Proteins/immunology ; RNA-Binding Proteins/chemistry ; RNA-Binding Proteins/genetics ; RNA-Binding Proteins/immunology ; Virus Internalization
Chemische Substanzen	IFITM3 protein, human ; Membrane Proteins ; RNA-Binding Proteins
Schlagwörter	covid19
Sprache	Englisch
Erscheinungsdatum	2020-10-28
Erscheinungsland	England
Dokumenttyp	Journal Article ; Research Support, N.I.H., Intramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2687154-3
ISSN	2050-084X ; 2050-084X
ISSN (online)	2050-084X
ISSN	2050-084X
DOI	10.7554/eLife.58537
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel ; Online: Homology-guided identification of a conserved motif linking the antiviral functions of IFITM3 to its oligomeric state

Rahman, Kazi / Coomer, Charles A. / Majdoul, Saliha / Ding, Selena / Padilla-Parra, Sergi / Compton, Alex A.

bioRxiv

Abstract	The interferon-inducible transmembrane (IFITM) proteins belong to the Dispanin/CD225 family and inhibit diverse virus infections. IFITM3 reduces membrane fusion between cells and virions through a poorly characterized mechanism. We identified a GxxxG motif in many CD225 proteins, including IFITM3 and proline rich transmembrane protein 2 (PRRT2). Mutation of PRRT2, a regulator of neurotransmitter release, at glycine-305 was previously linked to paroxysmal neurological disorders in humans. Here, we show that glycine-305 and the homologous site in IFITM3, glycine-95, drive protein oligomerization from within a GxxxG motif. Mutation of glycine-95 in IFITM3 disrupted its oligomerization and reduced its antiviral activity against Influenza A and HIV-1. The oligomerization-defective variant was used to reveal that IFITM3 promotes membrane rigidity in a glycine-95-dependent manner. Furthermore, a compound which counteracts virus inhibition by IFITM3, amphotericin B, prevented the IFITM3-mediated rigidification of membranes. Overall, these data suggest that IFITM3 oligomers inhibit virus-cell fusion by promoting membrane rigidity.
Schlagwörter	covid19
Verlag	BioRxiv
Dokumenttyp	Artikel ; Online
DOI	10.1101/2020.05.14.096891
Datenquelle	COVID19

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Artikel ; Online: IFITM3 Reduces Retroviral Envelope Abundance and Function and Is Counteracted by glycoGag.

Ahi, Yadvinder S / Yimer, Diborah / Shi, Guoli / Majdoul, Saliha / Rahman, Kazi / Rein, Alan / Compton, Alex A

mBio

2020 Band 11, Heft 1

Abstract: Interferon-induced transmembrane (IFITM) proteins are encoded by many vertebrate species and exhibit antiviral activities against a wide range of viruses. IFITM3, when present in virus-producing cells, reduces the fusion potential of HIV-1 virions, but ... ...

Abstract	Interferon-induced transmembrane (IFITM) proteins are encoded by many vertebrate species and exhibit antiviral activities against a wide range of viruses. IFITM3, when present in virus-producing cells, reduces the fusion potential of HIV-1 virions, but the mechanism is poorly understood. To define the breadth and mechanistic basis for the antiviral activity of IFITM3, we took advantage of a murine leukemia virus (MLV)-based pseudotyping system. By carefully controlling amounts of IFITM3 and envelope protein (Env) in virus-producing cells, we found that IFITM3 potently inhibits MLV infectivity when Env levels are limiting. Loss of infectivity was associated with defective proteolytic processing of Env and lysosomal degradation of the Env precursor. Ecotropic and xenotropic variants of MLV Env, as well as HIV-1 Env and vesicular stomatitis virus glycoprotein (VSV-G), are sensitive to IFITM3, whereas Ebola glycoprotein is resistant, suggesting that IFITM3 selectively inactivates certain viral glycoproteins. Furthermore, endogenous IFITM3 in human and murine cells negatively regulates MLV Env abundance. However, we found that the negative impact of IFITM3 on virion infectivity is greater than its impact on decreasing Env incorporation, suggesting that IFITM3 may impair Env function, as well as reduce the amount of Env in virions. Finally, we demonstrate that loss of virion infectivity mediated by IFITM3 is reversed by the expression of glycoGag, a murine retrovirus accessory protein previously shown to antagonize the antiviral activity of SERINC proteins. Overall, we show that IFITM3 impairs virion infectivity by regulating Env quantity and function but that enhanced Env expression and glycoGag confer viral resistance to IFITM3.
Mesh-Begriff(e)	Animals ; HIV-1/physiology ; Host-Pathogen Interactions/immunology ; Humans ; Immunity, Innate ; Leukemia Virus, Murine/physiology ; Lysosomes/metabolism ; Membrane Proteins/metabolism ; Mice ; Protein Binding ; Protein Transport ; Proteolysis ; RNA-Binding Proteins/metabolism ; Retroviridae/physiology ; Retroviridae Infections/immunology ; Retroviridae Infections/metabolism ; Retroviridae Infections/virology ; Viral Envelope Proteins/immunology ; Viral Envelope Proteins/metabolism
Chemische Substanzen	IFITM3 protein, human ; Membrane Proteins ; RNA-Binding Proteins ; Viral Envelope Proteins
Sprache	Englisch
Erscheinungsdatum	2020-01-21
Erscheinungsland	United States
Dokumenttyp	Journal Article
ZDB-ID	2557172-2
ISSN	2150-7511 ; 2161-2129
ISSN (online)	2150-7511
ISSN	2161-2129
DOI	10.1128/mBio.03088-19
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel ; Online: Constraints on Human CD34+ Cell Fate due to Lentiviral Vectors Can Be Relieved by Valproic Acid.

Moussy, Alice / Papili Gao, Nan / Corre, Guillaume / Poletti, Valentina / Majdoul, Saliha / Fenard, David / Gunawan, Rudiyanto / Stockholm, Daniel / Páldi, András

Human gene therapy

2019 Band 30, Heft 8, Seite(n) 1023–1034

Abstract: The initial stages following ... ...

Abstract	The initial stages following the
Mesh-Begriff(e)	Biomarkers ; Cell Differentiation/drug effects ; Fetal Blood/cytology ; Gene Expression ; Gene Transfer Techniques ; Genetic Vectors/genetics ; Hematopoietic Stem Cells/cytology ; Hematopoietic Stem Cells/drug effects ; Hematopoietic Stem Cells/metabolism ; Humans ; Lentivirus/genetics ; Phenotype ; Transduction, Genetic ; Transgenes ; Valproic Acid/pharmacology ; Virus Integration
Chemische Substanzen	Biomarkers ; Valproic Acid (614OI1Z5WI)
Sprache	Englisch
Erscheinungsdatum	2019-05-15
Erscheinungsland	United States
Dokumenttyp	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1028152-6
ISSN	1557-7422 ; 1043-0342
ISSN (online)	1557-7422
ISSN	1043-0342
DOI	10.1089/hum.2019.009
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel ; Online: Homology-guided identification of a conserved motif linking the antiviral functions of IFITM3 to its oligomeric state

Kazi Rahman / Charles A Coomer / Saliha Majdoul / Selena Y Ding / Sergi Padilla-Parra / Alex A Compton

eLife, Vol

2020 Band 9

Abstract	The interferon-inducible transmembrane (IFITM) proteins belong to the Dispanin/CD225 family and inhibit diverse virus infections. IFITM3 reduces membrane fusion between cells and virions through a poorly characterized mechanism. Mutation of proline-rich transmembrane protein 2 (PRRT2), a regulator of neurotransmitter release, at glycine-305 was previously linked to paroxysmal neurological disorders in humans. Here, we show that glycine-305 and the homologous site in IFITM3, glycine-95, drive protein oligomerization from within a GxxxG motif. Mutation of glycine-95 (and to a lesser extent, glycine-91) disrupted IFITM3 oligomerization and reduced its antiviral activity against Influenza A virus. An oligomerization-defective variant was used to reveal that IFITM3 promotes membrane rigidity in a glycine-95-dependent and amphipathic helix-dependent manner. Furthermore, a compound which counteracts virus inhibition by IFITM3, Amphotericin B, prevented the IFITM3-mediated rigidification of membranes. Overall, these data suggest that IFITM3 oligomers inhibit virus-cell fusion by promoting membrane rigidity.
Schlagwörter	membrane ; oligomerization ; IFITM ; virus ; PRRT2 ; fusion ; Medicine ; R ; Science ; Q ; Biology (General) ; QH301-705.5
Sprache	Englisch
Erscheinungsdatum	2020-10-01T00:00:00Z
Verlag	eLife Sciences Publications Ltd
Dokumenttyp	Artikel ; Online
Datenquelle	BASE - Bielefeld Academic Search Engine (Lebenswissenschaftliche Auswahl)

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Artikel: 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.
Sprache	Englisch
Erscheinungsdatum	2022-08-30
Erscheinungsland	United States
Dokumenttyp	Preprint
DOI	10.1101/2021.04.15.440067
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel ; 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 Band 132, Heft 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-Begriff(e)	Humans ; SARS-CoV-2 ; MTOR Inhibitors ; Virus Internalization ; COVID-19 ; Sirolimus/pharmacology ; Immunity, Innate ; Membrane Proteins ; RNA-Binding Proteins
Chemische Substanzen	MTOR Inhibitors ; ridaforolimus (48Z35KB15K) ; Sirolimus (W36ZG6FT64) ; IFITM2 protein, human ; Membrane Proteins ; IFITM3 protein, human ; RNA-Binding Proteins
Sprache	Englisch
Erscheinungsdatum	2022-12-15
Erscheinungsland	United States
Dokumenttyp	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
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel ; Online: Rapalogs downmodulate intrinsic immunity and promote cell entry of SARS-CoV-2

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

The Journal of Clinical Investigation, Vol 132, Iss

2022 Band 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, 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.
Schlagwörter	COVID-19 ; Medicine ; R
Thema/Rubrik (Code)	570
Sprache	Englisch
Erscheinungsdatum	2022-12-01T00:00:00Z
Verlag	American Society for Clinical Investigation
Dokumenttyp	Artikel ; Online
Datenquelle	BASE - Bielefeld Academic Search Engine (Lebenswissenschaftliche Auswahl)

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