The Experts below are selected from a list of 2034 Experts worldwide ranked by ideXlab platform
Jacob S. Yount - One of the best experts on this subject based on the ideXlab platform.
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mda5 participates in the detection of Paramyxovirus Infection and is essential for the early activation of dendritic cells in response to sendai virus defective interfering particles
Journal of Immunology, 2008Co-Authors: Jacob S. Yount, Leonid Gitlin, Thomas M Moran, Carolina B LopezAbstract:Defective interfering (DI) particles are byproducts of virus replication that potently enhance dendritic cell (DC) maturation by virus Infection. DI particles have been reported for many different viruses and are strong inducers of type I IFNs. The cellular mechanisms involved in the response to DI particles are not known. In this study, we show that 1) DI particles are recognized by more than one viral sensor independently of TLRs and type I IFN signaling; 2) The helicase MDA5 participates in the detection of DI genomes as MDA5-deficient DCs respond inefficiently to Sendai virus stocks containing DI particles; 3) DI particles stimulate the expression of IRF3-responsive genes by a uniquely potent mechanism when compared with other prototypic viral stimulus; and 4) the efficient detection of DI particles overcomes virus immune antagonism. These data highlight the outstanding adjuvant capacity of DI particles in stimulating mouse and human DCs. They also offer biological relevance to the previously reported inhibition of MDA5 by different Paramyxovirus V proteins. The unique mechanism by which DI particles trigger the maturation of DCs represents a novel strategy that could be further exploited for the development of potent adjuvant molecules.
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Cytokine-Independent Upregulation of MDA5 in Viral Infection
Journal of Virology, 2007Co-Authors: Jacob S. Yount, T.m. Moran, C. B. LopezAbstract:The RNA helicases RIG-I and MDA5 detect virus Infection of dendritic cells (DCs) leading to cytokine induction. Maximal sensitivity for virus detection by these helicases is obtained after their upregulation, which is thought to occur primarily through type I interferon (IFN) signaling. Here we demonstrate that in response to Paramyxovirus Infection, RIG-I upregulation requires type I IFN whereas MDA5 expression is increased by Sendai virus Infection independently of signaling mediated by type I IFN, STAT1, tumor necrosis factor alpha, or NF-kappaB. This MDA5 upregulation is largely lost in IRF3 knockout DCs and is achieved in type I IFN-deficient cells expressing constitutively active IRF3.
Douglas J Lamont - One of the best experts on this subject based on the ideXlab platform.
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the switch between acute and persistent Paramyxovirus Infection caused by single amino acid substitutions in the rna polymerase p subunit
PLOS Pathogens, 2019Co-Authors: Dan F Young, Elizabeth B Wignallfleming, David C Busse, Matthew J Pickin, Jack Hankinson, Elizabeth M Randall, Amy Tavendale, Andrew J Davison, Douglas J LamontAbstract:Paramyxoviruses can establish persistent Infections both in vitro and in vivo, some of which lead to chronic disease. However, little is known about the molecular events that contribute to the establishment of persistent Infections by RNA viruses. Using parainfluenza virus type 5 (PIV5) as a model we show that phosphorylation of the P protein, which is a key component of the viral RNA polymerase complex, determines whether or not viral transcription and replication becomes repressed at late times after Infection. If the virus becomes repressed, persistence is established, but if not, the infected cells die. We found that single amino acid changes at various positions within the P protein switched the Infection phenotype from lytic to persistent. Lytic variants replicated to higher titres in mice than persistent variants and caused greater infiltration of immune cells into infected lungs but were cleared more rapidly. We propose that during the acute phases of viral Infection in vivo, lytic variants of PIV5 will be selected but, as the adaptive immune response develops, variants in which viral replication can be repressed will be selected, leading to the establishment of prolonged, persistent Infections. We suggest that similar selection processes may operate for other RNA viruses.
Elizabeth B Wignallfleming - One of the best experts on this subject based on the ideXlab platform.
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the switch between acute and persistent Paramyxovirus Infection caused by single amino acid substitutions in the rna polymerase p subunit
PLOS Pathogens, 2019Co-Authors: Dan F Young, Elizabeth B Wignallfleming, David C Busse, Matthew J Pickin, Jack Hankinson, Elizabeth M Randall, Amy Tavendale, Andrew J Davison, Douglas J LamontAbstract:Paramyxoviruses can establish persistent Infections both in vitro and in vivo, some of which lead to chronic disease. However, little is known about the molecular events that contribute to the establishment of persistent Infections by RNA viruses. Using parainfluenza virus type 5 (PIV5) as a model we show that phosphorylation of the P protein, which is a key component of the viral RNA polymerase complex, determines whether or not viral transcription and replication becomes repressed at late times after Infection. If the virus becomes repressed, persistence is established, but if not, the infected cells die. We found that single amino acid changes at various positions within the P protein switched the Infection phenotype from lytic to persistent. Lytic variants replicated to higher titres in mice than persistent variants and caused greater infiltration of immune cells into infected lungs but were cleared more rapidly. We propose that during the acute phases of viral Infection in vivo, lytic variants of PIV5 will be selected but, as the adaptive immune response develops, variants in which viral replication can be repressed will be selected, leading to the establishment of prolonged, persistent Infections. We suggest that similar selection processes may operate for other RNA viruses.
Leonid Gitlin - One of the best experts on this subject based on the ideXlab platform.
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melanoma differentiation associated gene 5 mda5 is involved in the innate immune response to paramyxoviridae Infection in vivo
PLOS Pathogens, 2010Co-Authors: Leonid Gitlin, Loralyn A Benoit, Christina Song, Marina Cella, Susan Gilfillan, Michael J. Holtzman, Marco ColonnaAbstract:The early host response to pathogens is mediated by several distinct pattern recognition receptors. Cytoplasmic RNA helicases including RIG-I and MDA5 have been shown to respond to viral RNA by inducing interferon (IFN) production. Previous in vitro studies have demonstrated a direct role for MDA5 in the response to members of the Picornaviridae, Flaviviridae and Caliciviridae virus families ((+) ssRNA viruses) but not to Paramyxoviridae or Orthomyxoviridae ((−) ssRNA viruses). Contrary to these findings, we now show that MDA5 responds critically to Infections caused by Paramyxoviridae in vivo. Using an established model of natural Sendai virus (SeV) Infection, we demonstrate that MDA5−/− mice exhibit increased morbidity and mortality as well as severe histopathological changes in the lower airways in response to SeV. Moreover, analysis of viral propagation in the lungs of MDA5−/− mice reveals enhanced replication and a distinct distribution involving the interstitium. Though the levels of antiviral cytokines were comparable early during SeV Infection, type I, II, and III IFN mRNA expression profiles were significantly decreased in MDA5−/− mice by day 5 post Infection. Taken together, these findings indicate that MDA5 is indispensable for sustained expression of IFN in response to Paramyxovirus Infection and provide the first evidence of MDA5-dependent containment of in vivo Infections caused by (−) sense RNA viruses.
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mda5 participates in the detection of Paramyxovirus Infection and is essential for the early activation of dendritic cells in response to sendai virus defective interfering particles
Journal of Immunology, 2008Co-Authors: Jacob S. Yount, Leonid Gitlin, Thomas M Moran, Carolina B LopezAbstract:Defective interfering (DI) particles are byproducts of virus replication that potently enhance dendritic cell (DC) maturation by virus Infection. DI particles have been reported for many different viruses and are strong inducers of type I IFNs. The cellular mechanisms involved in the response to DI particles are not known. In this study, we show that 1) DI particles are recognized by more than one viral sensor independently of TLRs and type I IFN signaling; 2) The helicase MDA5 participates in the detection of DI genomes as MDA5-deficient DCs respond inefficiently to Sendai virus stocks containing DI particles; 3) DI particles stimulate the expression of IRF3-responsive genes by a uniquely potent mechanism when compared with other prototypic viral stimulus; and 4) the efficient detection of DI particles overcomes virus immune antagonism. These data highlight the outstanding adjuvant capacity of DI particles in stimulating mouse and human DCs. They also offer biological relevance to the previously reported inhibition of MDA5 by different Paramyxovirus V proteins. The unique mechanism by which DI particles trigger the maturation of DCs represents a novel strategy that could be further exploited for the development of potent adjuvant molecules.
Laura M Trejoavila - One of the best experts on this subject based on the ideXlab platform.
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sulphated polysaccharides from ulva clathrata and cladosiphon okamuranus seaweeds both inhibit viral attachment entry and cell cell fusion in ndv Infection
Marine Drugs, 2015Co-Authors: Jose Alberto Aguilarbriseno, Denis Ricquemarie, Edgar Mendozagamboa, Cristina Rodriguezpadilla, Jean-françois Sassi, Lucia Elizabeth Cruzsuarez, Pablo Zapatabenavides, Laura M TrejoavilaAbstract:Sulphated polysaccharides (SP) extracted from seaweeds have antiviral properties and are much less cytotoxic than conventional drugs, but little is known about their mode of action. Combination antiviral chemotherapy may offer advantages over single agent therapy, increasing efficiency, potency and delaying the emergence of resistant virus. The paramyxoviridae family includes pathogens causing morbidity and mortality worldwide in humans and animals, such as the Newcastle Disease Virus (NDV) in poultry. This study aims at determining the antiviral activity and mechanism of action in vitro of an ulvan (SP from the green seaweed Ulva clathrata), and of its mixture with a fucoidan (SP from Cladosiphon okamuranus), against La Sota NDV strain. The ulvan antiviral activity was tested using syncytia formation, exhibiting an IC50 of 0.1 μg/mL; ulvan had a better anti cell-cell spread effect than that previously shown for fucoidan, and inhibited cell-cell fusion via a direct effect on the F0 protein, but did not show any virucidal effect. The mixture of ulvan and fucoidan showed a greater anti-spread effect than SPs alone, but ulvan antagonizes the effect of fucoidan on the viral attachment/entry. Both SPs may be promising antivirals against Paramyxovirus Infection but their mixture has no clear synergistic advantage.