The Experts below are selected from a list of 8943 Experts worldwide ranked by ideXlab platform
Anna K Overby - One of the best experts on this subject based on the ideXlab platform.
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Cell-type- and region-specific restriction of neurotropic Flavivirus Infection by viperin
Journal of Neuroinflammation, 2018Co-Authors: Richard Lindqvist, Jonathan D. Gilthorpe, Chaitanya Kurhade, Anna K OverbyAbstract:Background Flaviviruses are a group of diverse and emerging arboviruses and an immense global health problem. A number of Flaviviruses are neurotropic, causing severe encephalitis and even death. Type I interferons (IFNs) are the first line of defense of the innate immune system against Flavivirus Infection. IFNs elicit the concerted action of numerous interferon-stimulated genes (ISGs) to restrict both virus Infection and replication. Viperin (virus-inhibitory protein, endoplasmic reticulum-associated, IFN-inducible) is an ISG with broad-spectrum antiviral activity against multiple Flaviviruses in vitro. Its activity in vivo restricts neurotropic Infections to specific regions of the central nervous system (CNS). However, the cell types in which viperin activity is required are unknown. Here we have examined both the regional and cell-type specificity of viperin in the defense against Infection by several model neurotropic Flaviviruses. Methods Viral burden and IFN induction were analyzed in vivo in wild-type and viperin^−/− mice infected with Langat virus (LGTV). The effects of IFN pretreatment were tested in vitro in primary neural cultures from different brain regions in response to Infection with tick-borne encephalitis virus (TBEV), West Nile virus (WNV), and Zika virus (ZIKV). Results Viperin activity restricted nonlethal LGTV Infection in the spleen and the olfactory bulb following Infection via a peripheral route. Viperin activity was also necessary to restrict LGTV replication in the olfactory bulb and the cerebrum following CNS Infection, but not in the cerebellum. In vitro, viperin could restrict TBEV replication in primary cortical neurons, but not in the cerebellar granule cell neurons. Interferon-induced viperin was also very important in primary cortical neurons to control TBEV, WNV, and ZIKV. Conclusions Our findings show that viperin restricts replication of neurotropic Flaviviruses in the CNS in a region- and cell-type-specific manner. The most important sites of activity are the olfactory bulb and cerebrum. Activity within the cerebrum is required in the cortical neurons in order to restrict spread. This study exemplifies cell type and regional diversity of the IFN response within the CNS and shows the importance of a potent broad-spectrum antiviral ISG.
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Cell-type- and region-specific restriction of neurotropic Flavivirus Infection by viperin
Journal of neuroinflammation, 2018Co-Authors: Richard Lindqvist, Jonathan D. Gilthorpe, Chaitanya Kurhade, Anna K OverbyAbstract:Flaviviruses are a group of diverse and emerging arboviruses and an immense global health problem. A number of Flaviviruses are neurotropic, causing severe encephalitis and even death. Type I interferons (IFNs) are the first line of defense of the innate immune system against Flavivirus Infection. IFNs elicit the concerted action of numerous interferon-stimulated genes (ISGs) to restrict both virus Infection and replication. Viperin (virus-inhibitory protein, endoplasmic reticulum-associated, IFN-inducible) is an ISG with broad-spectrum antiviral activity against multiple Flaviviruses in vitro. Its activity in vivo restricts neurotropic Infections to specific regions of the central nervous system (CNS). However, the cell types in which viperin activity is required are unknown. Here we have examined both the regional and cell-type specificity of viperin in the defense against Infection by several model neurotropic Flaviviruses. Viral burden and IFN induction were analyzed in vivo in wild-type and viperin−/− mice infected with Langat virus (LGTV). The effects of IFN pretreatment were tested in vitro in primary neural cultures from different brain regions in response to Infection with tick-borne encephalitis virus (TBEV), West Nile virus (WNV), and Zika virus (ZIKV). Viperin activity restricted nonlethal LGTV Infection in the spleen and the olfactory bulb following Infection via a peripheral route. Viperin activity was also necessary to restrict LGTV replication in the olfactory bulb and the cerebrum following CNS Infection, but not in the cerebellum. In vitro, viperin could restrict TBEV replication in primary cortical neurons, but not in the cerebellar granule cell neurons. Interferon-induced viperin was also very important in primary cortical neurons to control TBEV, WNV, and ZIKV. Our findings show that viperin restricts replication of neurotropic Flaviviruses in the CNS in a region- and cell-type-specific manner. The most important sites of activity are the olfactory bulb and cerebrum. Activity within the cerebrum is required in the cortical neurons in order to restrict spread. This study exemplifies cell type and regional diversity of the IFN response within the CNS and shows the importance of a potent broad-spectrum antiviral ISG.
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Fast type I interferon response protects astrocytes from Flavivirus Infection and virus-induced cytopathic effects
Journal of Neuroinflammation, 2016Co-Authors: Richard Lindqvist, Jonathan D. Gilthorpe, Andrea Kroger, Silke Wolfel, Filip Mundt, Nelson O. Gekara, Anna K OverbyAbstract:Background Neurotropic Flaviviruses such as tick-borne encephalitis virus (TBEV), Japanese encephalitis virus (JEV), West Nile virus (WNV), and Zika virus (ZIKV) are causative agents of severe brain-related diseases including meningitis, encephalitis, and microcephaly. We have previously shown that local type I interferon response within the central nervous system (CNS) is involved in the protection of mice against tick-borne Flavivirus Infection. However, the cells responsible for mounting this protective response are not defined.
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Fast type I interferon response protects astrocytes from Flavivirus Infection and virus-induced cytopathic effects
Journal of Neuroinflammation, 2016Co-Authors: Richard Lindqvist, Jonathan D. Gilthorpe, Andrea Kroger, Silke Wolfel, Filip Mundt, Nelson O. Gekara, Anna K OverbyAbstract:Background Neurotropic Flaviviruses such as tick-borne encephalitis virus (TBEV), Japanese encephalitis virus (JEV), West Nile virus (WNV), and Zika virus (ZIKV) are causative agents of severe brain-related diseases including meningitis, encephalitis, and microcephaly. We have previously shown that local type I interferon response within the central nervous system (CNS) is involved in the protection of mice against tick-borne Flavivirus Infection. However, the cells responsible for mounting this protective response are not defined. Methods Primary astrocytes were isolated from wild-type (WT) and interferon alpha receptor knock out (IFNAR^−/−) mice and infected with neurotropic Flaviviruses. Viral replication and spread, IFN induction and response, and cellular viability were analyzed. Transcriptional levels in primary astrocytes treated with interferon or supernatant from virus-infected cells were analyzed by RNA sequencing and evaluated by different bioinformatics tools. Results Here, we show that astrocytes control viral replication of different TBEV strains, JEV, WNV, and ZIKV. In contrast to fibroblast, astrocytes mount a rapid interferon response and restrict viral spread. Furthermore, basal expression levels of key interferon-stimulated genes are high in astrocytes compared to mouse embryonic fibroblasts. Bioinformatic analysis of RNA-sequencing data reveals that astrocytes have established a basal antiviral state which contributes to the rapid viral recognition and upregulation of interferons. The most highly upregulated pathways in neighboring cells were linked to type I interferon response and innate immunity. The restriction in viral growth was dependent on interferon signaling, since loss of the interferon receptor, or its blockade in wild-type cells, resulted in high viral replication and virus-induced cytopathic effects. Astrocyte supernatant from TBEV-infected cells can restrict TBEV growth in astrocytes already 6 h post Infection, the effect on neurons is highly reinforced, and astrocyte supernatant from 3 h post Infection is already protective. Conclusions These findings suggest that the combination of an intrinsic constitutive antiviral response and the fast induction of type I IFN production by astrocytes play an important role in self-protection of astrocytes and suppression of Flavivirus replication in the CNS.
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Fast type I interferon response protects astrocytes from Flavivirus Infection and virus-induced cytopathic effects.
Journal of neuroinflammation, 2016Co-Authors: Richard Lindqvist, Jonathan D. Gilthorpe, Andrea Kroger, Silke Wolfel, Filip Mundt, Nelson O. Gekara, Anna K OverbyAbstract:Neurotropic Flaviviruses such as tick-borne encephalitis virus (TBEV), Japanese encephalitis virus (JEV), West Nile virus (WNV), and Zika virus (ZIKV) are causative agents of severe brain-related diseases including meningitis, encephalitis, and microcephaly. We have previously shown that local type I interferon response within the central nervous system (CNS) is involved in the protection of mice against tick-borne Flavivirus Infection. However, the cells responsible for mounting this protective response are not defined. Primary astrocytes were isolated from wild-type (WT) and interferon alpha receptor knock out (IFNAR−/−) mice and infected with neurotropic Flaviviruses. Viral replication and spread, IFN induction and response, and cellular viability were analyzed. Transcriptional levels in primary astrocytes treated with interferon or supernatant from virus-infected cells were analyzed by RNA sequencing and evaluated by different bioinformatics tools. Here, we show that astrocytes control viral replication of different TBEV strains, JEV, WNV, and ZIKV. In contrast to fibroblast, astrocytes mount a rapid interferon response and restrict viral spread. Furthermore, basal expression levels of key interferon-stimulated genes are high in astrocytes compared to mouse embryonic fibroblasts. Bioinformatic analysis of RNA-sequencing data reveals that astrocytes have established a basal antiviral state which contributes to the rapid viral recognition and upregulation of interferons. The most highly upregulated pathways in neighboring cells were linked to type I interferon response and innate immunity. The restriction in viral growth was dependent on interferon signaling, since loss of the interferon receptor, or its blockade in wild-type cells, resulted in high viral replication and virus-induced cytopathic effects. Astrocyte supernatant from TBEV-infected cells can restrict TBEV growth in astrocytes already 6 h post Infection, the effect on neurons is highly reinforced, and astrocyte supernatant from 3 h post Infection is already protective. These findings suggest that the combination of an intrinsic constitutive antiviral response and the fast induction of type I IFN production by astrocytes play an important role in self-protection of astrocytes and suppression of Flavivirus replication in the CNS.
Richard Lindqvist - One of the best experts on this subject based on the ideXlab platform.
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Cell-type- and region-specific restriction of neurotropic Flavivirus Infection by viperin
Journal of Neuroinflammation, 2018Co-Authors: Richard Lindqvist, Jonathan D. Gilthorpe, Chaitanya Kurhade, Anna K OverbyAbstract:Background Flaviviruses are a group of diverse and emerging arboviruses and an immense global health problem. A number of Flaviviruses are neurotropic, causing severe encephalitis and even death. Type I interferons (IFNs) are the first line of defense of the innate immune system against Flavivirus Infection. IFNs elicit the concerted action of numerous interferon-stimulated genes (ISGs) to restrict both virus Infection and replication. Viperin (virus-inhibitory protein, endoplasmic reticulum-associated, IFN-inducible) is an ISG with broad-spectrum antiviral activity against multiple Flaviviruses in vitro. Its activity in vivo restricts neurotropic Infections to specific regions of the central nervous system (CNS). However, the cell types in which viperin activity is required are unknown. Here we have examined both the regional and cell-type specificity of viperin in the defense against Infection by several model neurotropic Flaviviruses. Methods Viral burden and IFN induction were analyzed in vivo in wild-type and viperin^−/− mice infected with Langat virus (LGTV). The effects of IFN pretreatment were tested in vitro in primary neural cultures from different brain regions in response to Infection with tick-borne encephalitis virus (TBEV), West Nile virus (WNV), and Zika virus (ZIKV). Results Viperin activity restricted nonlethal LGTV Infection in the spleen and the olfactory bulb following Infection via a peripheral route. Viperin activity was also necessary to restrict LGTV replication in the olfactory bulb and the cerebrum following CNS Infection, but not in the cerebellum. In vitro, viperin could restrict TBEV replication in primary cortical neurons, but not in the cerebellar granule cell neurons. Interferon-induced viperin was also very important in primary cortical neurons to control TBEV, WNV, and ZIKV. Conclusions Our findings show that viperin restricts replication of neurotropic Flaviviruses in the CNS in a region- and cell-type-specific manner. The most important sites of activity are the olfactory bulb and cerebrum. Activity within the cerebrum is required in the cortical neurons in order to restrict spread. This study exemplifies cell type and regional diversity of the IFN response within the CNS and shows the importance of a potent broad-spectrum antiviral ISG.
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Cell-type- and region-specific restriction of neurotropic Flavivirus Infection by viperin
Journal of neuroinflammation, 2018Co-Authors: Richard Lindqvist, Jonathan D. Gilthorpe, Chaitanya Kurhade, Anna K OverbyAbstract:Flaviviruses are a group of diverse and emerging arboviruses and an immense global health problem. A number of Flaviviruses are neurotropic, causing severe encephalitis and even death. Type I interferons (IFNs) are the first line of defense of the innate immune system against Flavivirus Infection. IFNs elicit the concerted action of numerous interferon-stimulated genes (ISGs) to restrict both virus Infection and replication. Viperin (virus-inhibitory protein, endoplasmic reticulum-associated, IFN-inducible) is an ISG with broad-spectrum antiviral activity against multiple Flaviviruses in vitro. Its activity in vivo restricts neurotropic Infections to specific regions of the central nervous system (CNS). However, the cell types in which viperin activity is required are unknown. Here we have examined both the regional and cell-type specificity of viperin in the defense against Infection by several model neurotropic Flaviviruses. Viral burden and IFN induction were analyzed in vivo in wild-type and viperin−/− mice infected with Langat virus (LGTV). The effects of IFN pretreatment were tested in vitro in primary neural cultures from different brain regions in response to Infection with tick-borne encephalitis virus (TBEV), West Nile virus (WNV), and Zika virus (ZIKV). Viperin activity restricted nonlethal LGTV Infection in the spleen and the olfactory bulb following Infection via a peripheral route. Viperin activity was also necessary to restrict LGTV replication in the olfactory bulb and the cerebrum following CNS Infection, but not in the cerebellum. In vitro, viperin could restrict TBEV replication in primary cortical neurons, but not in the cerebellar granule cell neurons. Interferon-induced viperin was also very important in primary cortical neurons to control TBEV, WNV, and ZIKV. Our findings show that viperin restricts replication of neurotropic Flaviviruses in the CNS in a region- and cell-type-specific manner. The most important sites of activity are the olfactory bulb and cerebrum. Activity within the cerebrum is required in the cortical neurons in order to restrict spread. This study exemplifies cell type and regional diversity of the IFN response within the CNS and shows the importance of a potent broad-spectrum antiviral ISG.
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The role of the type I interferons and viperin during neurotropic Flavivirus Infection
2017Co-Authors: Richard LindqvistAbstract:Flaviviruses are globally distributed pathogens that cause millions of human Infections annually. One of the most detrimental outcomes of Flavivirus Infection is encephalitis, which is caused by ne ...
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Fast type I interferon response protects astrocytes from Flavivirus Infection and virus-induced cytopathic effects
Journal of Neuroinflammation, 2016Co-Authors: Richard Lindqvist, Jonathan D. Gilthorpe, Andrea Kroger, Silke Wolfel, Filip Mundt, Nelson O. Gekara, Anna K OverbyAbstract:Background Neurotropic Flaviviruses such as tick-borne encephalitis virus (TBEV), Japanese encephalitis virus (JEV), West Nile virus (WNV), and Zika virus (ZIKV) are causative agents of severe brain-related diseases including meningitis, encephalitis, and microcephaly. We have previously shown that local type I interferon response within the central nervous system (CNS) is involved in the protection of mice against tick-borne Flavivirus Infection. However, the cells responsible for mounting this protective response are not defined.
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Fast type I interferon response protects astrocytes from Flavivirus Infection and virus-induced cytopathic effects
Journal of Neuroinflammation, 2016Co-Authors: Richard Lindqvist, Jonathan D. Gilthorpe, Andrea Kroger, Silke Wolfel, Filip Mundt, Nelson O. Gekara, Anna K OverbyAbstract:Background Neurotropic Flaviviruses such as tick-borne encephalitis virus (TBEV), Japanese encephalitis virus (JEV), West Nile virus (WNV), and Zika virus (ZIKV) are causative agents of severe brain-related diseases including meningitis, encephalitis, and microcephaly. We have previously shown that local type I interferon response within the central nervous system (CNS) is involved in the protection of mice against tick-borne Flavivirus Infection. However, the cells responsible for mounting this protective response are not defined. Methods Primary astrocytes were isolated from wild-type (WT) and interferon alpha receptor knock out (IFNAR^−/−) mice and infected with neurotropic Flaviviruses. Viral replication and spread, IFN induction and response, and cellular viability were analyzed. Transcriptional levels in primary astrocytes treated with interferon or supernatant from virus-infected cells were analyzed by RNA sequencing and evaluated by different bioinformatics tools. Results Here, we show that astrocytes control viral replication of different TBEV strains, JEV, WNV, and ZIKV. In contrast to fibroblast, astrocytes mount a rapid interferon response and restrict viral spread. Furthermore, basal expression levels of key interferon-stimulated genes are high in astrocytes compared to mouse embryonic fibroblasts. Bioinformatic analysis of RNA-sequencing data reveals that astrocytes have established a basal antiviral state which contributes to the rapid viral recognition and upregulation of interferons. The most highly upregulated pathways in neighboring cells were linked to type I interferon response and innate immunity. The restriction in viral growth was dependent on interferon signaling, since loss of the interferon receptor, or its blockade in wild-type cells, resulted in high viral replication and virus-induced cytopathic effects. Astrocyte supernatant from TBEV-infected cells can restrict TBEV growth in astrocytes already 6 h post Infection, the effect on neurons is highly reinforced, and astrocyte supernatant from 3 h post Infection is already protective. Conclusions These findings suggest that the combination of an intrinsic constitutive antiviral response and the fast induction of type I IFN production by astrocytes play an important role in self-protection of astrocytes and suppression of Flavivirus replication in the CNS.
Jonathan D. Gilthorpe - One of the best experts on this subject based on the ideXlab platform.
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Cell-type- and region-specific restriction of neurotropic Flavivirus Infection by viperin
Journal of Neuroinflammation, 2018Co-Authors: Richard Lindqvist, Jonathan D. Gilthorpe, Chaitanya Kurhade, Anna K OverbyAbstract:Background Flaviviruses are a group of diverse and emerging arboviruses and an immense global health problem. A number of Flaviviruses are neurotropic, causing severe encephalitis and even death. Type I interferons (IFNs) are the first line of defense of the innate immune system against Flavivirus Infection. IFNs elicit the concerted action of numerous interferon-stimulated genes (ISGs) to restrict both virus Infection and replication. Viperin (virus-inhibitory protein, endoplasmic reticulum-associated, IFN-inducible) is an ISG with broad-spectrum antiviral activity against multiple Flaviviruses in vitro. Its activity in vivo restricts neurotropic Infections to specific regions of the central nervous system (CNS). However, the cell types in which viperin activity is required are unknown. Here we have examined both the regional and cell-type specificity of viperin in the defense against Infection by several model neurotropic Flaviviruses. Methods Viral burden and IFN induction were analyzed in vivo in wild-type and viperin^−/− mice infected with Langat virus (LGTV). The effects of IFN pretreatment were tested in vitro in primary neural cultures from different brain regions in response to Infection with tick-borne encephalitis virus (TBEV), West Nile virus (WNV), and Zika virus (ZIKV). Results Viperin activity restricted nonlethal LGTV Infection in the spleen and the olfactory bulb following Infection via a peripheral route. Viperin activity was also necessary to restrict LGTV replication in the olfactory bulb and the cerebrum following CNS Infection, but not in the cerebellum. In vitro, viperin could restrict TBEV replication in primary cortical neurons, but not in the cerebellar granule cell neurons. Interferon-induced viperin was also very important in primary cortical neurons to control TBEV, WNV, and ZIKV. Conclusions Our findings show that viperin restricts replication of neurotropic Flaviviruses in the CNS in a region- and cell-type-specific manner. The most important sites of activity are the olfactory bulb and cerebrum. Activity within the cerebrum is required in the cortical neurons in order to restrict spread. This study exemplifies cell type and regional diversity of the IFN response within the CNS and shows the importance of a potent broad-spectrum antiviral ISG.
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Cell-type- and region-specific restriction of neurotropic Flavivirus Infection by viperin
Journal of neuroinflammation, 2018Co-Authors: Richard Lindqvist, Jonathan D. Gilthorpe, Chaitanya Kurhade, Anna K OverbyAbstract:Flaviviruses are a group of diverse and emerging arboviruses and an immense global health problem. A number of Flaviviruses are neurotropic, causing severe encephalitis and even death. Type I interferons (IFNs) are the first line of defense of the innate immune system against Flavivirus Infection. IFNs elicit the concerted action of numerous interferon-stimulated genes (ISGs) to restrict both virus Infection and replication. Viperin (virus-inhibitory protein, endoplasmic reticulum-associated, IFN-inducible) is an ISG with broad-spectrum antiviral activity against multiple Flaviviruses in vitro. Its activity in vivo restricts neurotropic Infections to specific regions of the central nervous system (CNS). However, the cell types in which viperin activity is required are unknown. Here we have examined both the regional and cell-type specificity of viperin in the defense against Infection by several model neurotropic Flaviviruses. Viral burden and IFN induction were analyzed in vivo in wild-type and viperin−/− mice infected with Langat virus (LGTV). The effects of IFN pretreatment were tested in vitro in primary neural cultures from different brain regions in response to Infection with tick-borne encephalitis virus (TBEV), West Nile virus (WNV), and Zika virus (ZIKV). Viperin activity restricted nonlethal LGTV Infection in the spleen and the olfactory bulb following Infection via a peripheral route. Viperin activity was also necessary to restrict LGTV replication in the olfactory bulb and the cerebrum following CNS Infection, but not in the cerebellum. In vitro, viperin could restrict TBEV replication in primary cortical neurons, but not in the cerebellar granule cell neurons. Interferon-induced viperin was also very important in primary cortical neurons to control TBEV, WNV, and ZIKV. Our findings show that viperin restricts replication of neurotropic Flaviviruses in the CNS in a region- and cell-type-specific manner. The most important sites of activity are the olfactory bulb and cerebrum. Activity within the cerebrum is required in the cortical neurons in order to restrict spread. This study exemplifies cell type and regional diversity of the IFN response within the CNS and shows the importance of a potent broad-spectrum antiviral ISG.
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Fast type I interferon response protects astrocytes from Flavivirus Infection and virus-induced cytopathic effects
Journal of Neuroinflammation, 2016Co-Authors: Richard Lindqvist, Jonathan D. Gilthorpe, Andrea Kroger, Silke Wolfel, Filip Mundt, Nelson O. Gekara, Anna K OverbyAbstract:Background Neurotropic Flaviviruses such as tick-borne encephalitis virus (TBEV), Japanese encephalitis virus (JEV), West Nile virus (WNV), and Zika virus (ZIKV) are causative agents of severe brain-related diseases including meningitis, encephalitis, and microcephaly. We have previously shown that local type I interferon response within the central nervous system (CNS) is involved in the protection of mice against tick-borne Flavivirus Infection. However, the cells responsible for mounting this protective response are not defined.
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Fast type I interferon response protects astrocytes from Flavivirus Infection and virus-induced cytopathic effects
Journal of Neuroinflammation, 2016Co-Authors: Richard Lindqvist, Jonathan D. Gilthorpe, Andrea Kroger, Silke Wolfel, Filip Mundt, Nelson O. Gekara, Anna K OverbyAbstract:Background Neurotropic Flaviviruses such as tick-borne encephalitis virus (TBEV), Japanese encephalitis virus (JEV), West Nile virus (WNV), and Zika virus (ZIKV) are causative agents of severe brain-related diseases including meningitis, encephalitis, and microcephaly. We have previously shown that local type I interferon response within the central nervous system (CNS) is involved in the protection of mice against tick-borne Flavivirus Infection. However, the cells responsible for mounting this protective response are not defined. Methods Primary astrocytes were isolated from wild-type (WT) and interferon alpha receptor knock out (IFNAR^−/−) mice and infected with neurotropic Flaviviruses. Viral replication and spread, IFN induction and response, and cellular viability were analyzed. Transcriptional levels in primary astrocytes treated with interferon or supernatant from virus-infected cells were analyzed by RNA sequencing and evaluated by different bioinformatics tools. Results Here, we show that astrocytes control viral replication of different TBEV strains, JEV, WNV, and ZIKV. In contrast to fibroblast, astrocytes mount a rapid interferon response and restrict viral spread. Furthermore, basal expression levels of key interferon-stimulated genes are high in astrocytes compared to mouse embryonic fibroblasts. Bioinformatic analysis of RNA-sequencing data reveals that astrocytes have established a basal antiviral state which contributes to the rapid viral recognition and upregulation of interferons. The most highly upregulated pathways in neighboring cells were linked to type I interferon response and innate immunity. The restriction in viral growth was dependent on interferon signaling, since loss of the interferon receptor, or its blockade in wild-type cells, resulted in high viral replication and virus-induced cytopathic effects. Astrocyte supernatant from TBEV-infected cells can restrict TBEV growth in astrocytes already 6 h post Infection, the effect on neurons is highly reinforced, and astrocyte supernatant from 3 h post Infection is already protective. Conclusions These findings suggest that the combination of an intrinsic constitutive antiviral response and the fast induction of type I IFN production by astrocytes play an important role in self-protection of astrocytes and suppression of Flavivirus replication in the CNS.
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Fast type I interferon response protects astrocytes from Flavivirus Infection and virus-induced cytopathic effects.
Journal of neuroinflammation, 2016Co-Authors: Richard Lindqvist, Jonathan D. Gilthorpe, Andrea Kroger, Silke Wolfel, Filip Mundt, Nelson O. Gekara, Anna K OverbyAbstract:Neurotropic Flaviviruses such as tick-borne encephalitis virus (TBEV), Japanese encephalitis virus (JEV), West Nile virus (WNV), and Zika virus (ZIKV) are causative agents of severe brain-related diseases including meningitis, encephalitis, and microcephaly. We have previously shown that local type I interferon response within the central nervous system (CNS) is involved in the protection of mice against tick-borne Flavivirus Infection. However, the cells responsible for mounting this protective response are not defined. Primary astrocytes were isolated from wild-type (WT) and interferon alpha receptor knock out (IFNAR−/−) mice and infected with neurotropic Flaviviruses. Viral replication and spread, IFN induction and response, and cellular viability were analyzed. Transcriptional levels in primary astrocytes treated with interferon or supernatant from virus-infected cells were analyzed by RNA sequencing and evaluated by different bioinformatics tools. Here, we show that astrocytes control viral replication of different TBEV strains, JEV, WNV, and ZIKV. In contrast to fibroblast, astrocytes mount a rapid interferon response and restrict viral spread. Furthermore, basal expression levels of key interferon-stimulated genes are high in astrocytes compared to mouse embryonic fibroblasts. Bioinformatic analysis of RNA-sequencing data reveals that astrocytes have established a basal antiviral state which contributes to the rapid viral recognition and upregulation of interferons. The most highly upregulated pathways in neighboring cells were linked to type I interferon response and innate immunity. The restriction in viral growth was dependent on interferon signaling, since loss of the interferon receptor, or its blockade in wild-type cells, resulted in high viral replication and virus-induced cytopathic effects. Astrocyte supernatant from TBEV-infected cells can restrict TBEV growth in astrocytes already 6 h post Infection, the effect on neurons is highly reinforced, and astrocyte supernatant from 3 h post Infection is already protective. These findings suggest that the combination of an intrinsic constitutive antiviral response and the fast induction of type I IFN production by astrocytes play an important role in self-protection of astrocytes and suppression of Flavivirus replication in the CNS.
Pei Yong Shi - One of the best experts on this subject based on the ideXlab platform.
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A virus-type specific serological diagnosis of Flavivirus Infection using virus-like particles
Virologica Sinica, 2009Co-Authors: Min Qing, Zhiming Yuan, Pei Yong ShiAbstract:Many Flaviviruses are emerging and reemerging pathogens, such as West Nile virus (WNV), dengue virus (DENV), yellow fever virus (YFV), and Japanese encephalitis virus. Serological assay is the dominant method for diagnosis of Flavivirus Infections in human. Because antibodies generated during Flavivirus Infections cross-react with other Flavivirus members, plaque reduction neutralization test (PRNT) is the only available assay to determine the infecting Flavivirus type. Since PRNT requires culturing raw viruses, it must be performed in biosafety level-3 or level-4 containment for many Flaviviruses, and takes more than ten days to complete. To overcome these problems, we have developed Flavivirus viral-like particles (VLPs) that could be used to replace raw viruses in the neutralization assay. The VLPs were prepared by trans packaging a luciferase-reporting replicon with viral structural proteins. This novel assay involves three simple steps: (i) VLPs from a panel of Flaviviruses are incubated with Flavivirus-infected sera at 37°C for 1 h; (ii)the neutralized VLPs are used to infect Vero cells; and (iii) the infected cells are measured for luciferase activities at 22 h post-Infection. The virus type whose VLP is most efficiently neutralized by the serum specimen (as quantified by the luciferase activities) is the etiologic agent. As a proof-of-concept, we show that a WNV-infected mouse serum neutralized the WNV VLP more efficiently and selectively than the DENV and YFV VLPs. Our results demonstrate that the VLP neutralization assay maintains the “gold standard” of the classic PRNT; importantly, it shortens the assay time from >10 days to
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a virus type specific serological diagnosis of Flavivirus Infection using virus like particles
Virologica Sinica, 2009Co-Authors: Min Qing, Zhiming Yuan, Pei Yong ShiAbstract:Many Flaviviruses are emerging and reemerging pathogens, such as West Nile virus (WNV), dengue virus (DENV), yellow fever virus (YFV), and Japanese encephalitis virus. Serological assay is the dominant method for diagnosis of Flavivirus Infections in human. Because antibodies generated during Flavivirus Infections cross-react with other Flavivirus members, plaque reduction neutralization test (PRNT) is the only available assay to determine the infecting Flavivirus type. Since PRNT requires culturing raw viruses, it must be performed in biosafety level-3 or level-4 containment for many Flaviviruses, and takes more than ten days to complete. To overcome these problems, we have developed Flavivirus viral-like particles (VLPs) that could be used to replace raw viruses in the neutralization assay. The VLPs were prepared by trans packaging a luciferase-reporting replicon with viral structural proteins. This novel assay involves three simple steps: (i) VLPs from a panel of Flaviviruses are incubated with Flavivirus-infected sera at 37°C for 1 h; (ii)the neutralized VLPs are used to infect Vero cells; and (iii) the infected cells are measured for luciferase activities at 22 h post-Infection. The virus type whose VLP is most efficiently neutralized by the serum specimen (as quantified by the luciferase activities) is the etiologic agent. As a proof-of-concept, we show that a WNV-infected mouse serum neutralized the WNV VLP more efficiently and selectively than the DENV and YFV VLPs. Our results demonstrate that the VLP neutralization assay maintains the “gold standard” of the classic PRNT; importantly, it shortens the assay time from >10 days to <1 day, and can be performed in biosafety level-2 facility.
Michael S. Diamond - One of the best experts on this subject based on the ideXlab platform.
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Intestinal Dysmotility Syndromes following Systemic Infection by Flaviviruses.
Cell, 2018Co-Authors: James P. White, Shanshan Xiong, Nicole P. Malvin, William Khoury-hanold, Robert O. Heuckeroth, Thaddeus S. Stappenbeck, Michael S. DiamondAbstract:Although chronic gastrointestinal dysmotility syndromes are a common worldwide health problem, underlying causes for these disorders are poorly understood. We show that Flavivirus Infection of enteric neurons leads to acute neuronal injury and cell death, inflammation, bowel dilation, and slowing of intestinal transit in mice. Flavivirus-primed CD8+ T cells promote these phenotypes, as their absence diminished enteric neuron injury and intestinal transit delays, and their adoptive transfer reestablished dysmotility after Flavivirus Infection. Remarkably, mice surviving acute Flavivirus Infection developed chronic gastrointestinal dysmotility that was exacerbated by immunization with an unrelated alphavirus vaccine or exposure to a non-infectious inflammatory stimulus. This model of chronic post-infectious gastrointestinal dysmotility in mice suggests that viral Infections with tropism for enteric neurons and the ensuing immune response might contribute to the development of bowel motility disorders in humans. These results suggest an opportunity for unique approaches to diagnosis and therapy of gastrointestinal dysmotility syndromes.
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a game of numbers the stoichiometry of antibody mediated neutralization of Flavivirus Infection
Progress in Molecular Biology and Translational Science, 2015Co-Authors: Theodore C. Pierson, Michael S. DiamondAbstract:The humoral response contributes to the protection against viral pathogens. Although antibodies have the potential to inhibit viral Infections via several mechanisms, an ability to neutralize viruses directly may be particularly important. Neutralizing antibody titers are commonly used as predictors of protection from Infection, especially in the context of vaccine responses and immunity. Despite the simplicity of the concept, how antibody binding results in virus inactivation is incompletely understood despite decades of research. Flaviviruses have been an attractive system in which to seek a structural and quantitative understanding of how antibody interactions with virions modulate Infection because of the contribution of antibodies to both protection and pathogenesis. This review will present a stoichiometric model of antibody-mediated neutralization of Flaviviruses and discuss how these concepts can inform the development of vaccines and antibody-based therapeutics.
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Direct Complement Restriction of Flavivirus Infection Requires Glycan Recognition by Mannose-Binding Lectin
Cell host & microbe, 2010Co-Authors: Anja Fuchs, Theodore C. Pierson, Tsai-yu Lin, David W.c. Beasley, Cordula M. Stover, Wilhelm J. Schwaeble, Michael S. DiamondAbstract:Summary An intact complement system is crucial for limiting West Nile virus (WNV) dissemination. Herein, we define how complement directly restricts Flavivirus Infection in an antibody-independent fashion. Mannose-binding lectin (MBL) recognized N-linked glycans on the structural proteins of WNV and Dengue virus (DENV), resulting in neutralization through a C3- and C4-dependent mechanism that utilized both the canonical and bypass lectin activation pathways. For WNV, neutralization occurred with virus produced in insect cells, whereas for DENV, neutralization of insect and mammalian cell-derived virus was observed. Mechanism of action studies suggested that the MBL-dependent neutralization occurred, in part, by blocking viral fusion. Experiments in mice showed an MBL-dependent accelerated intravascular clearance of DENV or a WNV mutant with two N-linked glycans on its E protein, but not with wild-type WNV. Our studies show that MBL recognizes terminal mannose-containing carbohydrates on Flaviviruses, resulting in neutralization and efficient clearance in vivo.
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Molecular mechanisms of antibody-mediated neutralisation of Flavivirus Infection.
Expert reviews in molecular medicine, 2008Co-Authors: Theodore C. Pierson, Michael S. DiamondAbstract:Flaviviruses are a group of positive-stranded RNA viruses that cause a spectrum of severe illnesses globally in more than 50 million individuals each year. While effective vaccines exist for three members of this group (yellow fever, Japanese encephalitis, and tick-borne encephalitis viruses), safe and effective vaccines for several other Flaviviruses of clinical importance, including West Nile and dengue viruses, remain in development. An effective humoral immune response is critical for protection against Flaviviruses and an essential goal of vaccine development. The effectiveness of virus-specific antibodies in vivo reflects their capacity to inhibit virus entry and spread through several mechanisms, including the direct neutralisation of virus Infection. Recent advances in our understanding of the structural biology of Flaviviruses, coupled with the use of small-animal models of Flavivirus Infection, have promoted significant advances in our appreciation of the factors that govern antibody recognition and inhibition of Flaviviruses in vitro and in vivo. In this review, we discuss the properties that define the potency of neutralising antibodies and the molecular mechanisms by which they inhibit virus Infection. How recent advances in this area have the potential to improve the development of safe and effective vaccines and immunotherapeutics is also addressed.
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Complement Protein C1q Inhibits Antibody-Dependent Enhancement of Flavivirus Infection in an IgG Subclass-Specific Manner
Cell host & microbe, 2007Co-Authors: Erin Mehlhop, Theodore C. Pierson, Camilo Ansarah-sobrinho, Syd Johnson, Michael Engle, Daved H. Fremont, Michael S. DiamondAbstract:Severe dengue virus Infection can occur in humans with pre-existing antibodies against the virus. This observation led to the hypothesis that a subneutralizing antibody level in vivo can increase viral burden and cause more severe disease. Indeed, antibody-dependent enhancement of Infection (ADE) in vitro has been described for multiple viruses, including the Flaviviruses dengue virus and West Nile virus. Here, we demonstrate that the complement component C1q restricts ADE by anti-Flavivirus IgG antibodies in an IgG subclass-specific manner in cell culture and in mice. IgG subclasses that avidly bind C1q induced minimal ADE in the presence of C1q. These findings add a layer of complexity for the analysis of humoral immunity and Flavivirus Infection.