Interferon Regulatory Factor-1 Protects from Fatal Neurotropic Infection with Vesicular Stomatitis Virus by Specific Inhibition of Viral Replication in Neurons
Publication Date
March 27, 2014
Journal
PLOS Pathogens
Authors
Sharmila Nair, Kristin Michaelsen Preusse, Katja Finsterbusch, Sabine Stegemann Koniszewski, et al
Volume
10
Issue
3
Pages
e1003999
DOI
https://dx.plos.org/10.1371/journal.ppat.1003999
Publisher URL
http://journals.plos.org/plospathogens/article?id=10.1371%2Fjournal.ppat.1003999
PubMed
http://www.ncbi.nlm.nih.gov/pubmed/24675692
PubMed Central
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3968136
Europe PMC
http://europepmc.org/abstract/MED/24675692
Web of Science
000337470300042
Scopus
84897382155
Mendeley
http://www.mendeley.com/research/interferon-regulatory-factor1-protects-fatal-neurotropic-infection-vesicular-stomatitis-virus-specif
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Mendeley | Further Information

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Scopus | Further Information

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/1439506"], "description"=>"<p>A, WT and IRF-1<sup>−/−</sup> mice were infected intranasally with 5×10<sup>6</sup> pfu VSV and serum samples were collected at the indicated time points. IgM and IgG titers were quantitated by the virus neutralization assay. B/C/D, WT and IRF-1<sup>−/−</sup> mice were lethally irradiated and reconstituted with bone marrow from IRF-1<sup>−/−</sup> or WT mice, respectively. After 6–8 weeks, chimeric mice were infected intranasally with 5×10<sup>6</sup> pfu VSV. B, Survival was monitored and plotted as Kaplan-Meier curves (n = 8–10). Data are representative of two independent experiments. Survival differences were tested for statistical significance by the log-rank test, * p<0.05. C,D Leukocytes were isolated from brains of chimeric mice (n = 6–9) 6 days post infection, stained for CD45.1 and CD8, and analyzed by flow cytometry, C, Representative flow cytometry profiles of WT CD8<sup>+</sup> T cells from donor hematopoietic cells in the recipient irradiated WT and IRF-1<sup>−/−</sup> mice. D, Total cell numbers for infiltrating donor WT CD8+ T cells in the brains of recipient WT and IRF-1<sup>−/−</sup> mice.</p>", "links"=>[], "tags"=>["Infectious diseases", "Infectious disease control", "Viral diseases", "anti-viral", "irf-1", "driven", "adaptive", "responses", "hematopoietic"], "article_id"=>977760, "categories"=>["Medicine"], "users"=>["Sharmila Nair", "Kristin Michaelsen-Preusse", "Katja Finsterbusch", "Sabine Stegemann-Koniszewski", "Dunja Bruder", "Martina Grashoff", "Martin Korte", "Mario Köster", "Ulrich Kalinke", "Hansjörg Hauser", "Andrea Kröger"], "doi"=>"https://dx.doi.org/10.1371/journal.ppat.1003999.g003", "stats"=>{"downloads"=>4, "page_views"=>10, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_The_anti_viral_effects_of_IRF_1_are_neither_driven_by_the_adaptive_immune_responses_nor_by_the_hematopoietic_cells_/977760", "title"=>"The anti-viral effects of IRF-1 are neither driven by the adaptive immune responses nor by the hematopoietic cells.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-03-27 04:25:00"}
  • {"files"=>["https://ndownloader.figshare.com/files/1439525", "https://ndownloader.figshare.com/files/1439526", "https://ndownloader.figshare.com/files/1439527"], "description"=>"<div><p>The innate immune system protects cells against invading viral pathogens by the auto- and paracrine action of type I interferon (IFN). In addition, the interferon regulatory factor (IRF)-1 can induce alternative intrinsic antiviral responses. Although both, type I IFN and IRF-1 mediate their antiviral action by inducing overlapping subsets of IFN stimulated genes, the functional role of this alternative antiviral action of IRF-1 in context of viral infections <i>in vivo</i> remains unknown. Here, we report that IRF-1 is essential to counteract the neuropathology of vesicular stomatitis virus (VSV). IFN- and IRF-1-dependent antiviral responses act sequentially to create a layered antiviral protection program against VSV infections. Upon intranasal infection, VSV is cleared in the presence or absence of IRF-1 in peripheral organs, but IRF-1<sup>−/−</sup> mice continue to propagate the virus in the brain and succumb. Although rapid IFN induction leads to a decline in VSV titers early on, viral replication is re-enforced in the brains of IRF-1<sup>−/−</sup> mice. While IFN provides short-term protection, IRF-1 is induced with delayed kinetics and controls viral replication at later stages of infection. IRF-1 has no influence on viral entry but inhibits viral replication in neurons and viral spread through the CNS, which leads to fatal inflammatory responses in the CNS. These data support a temporal, non-redundant antiviral function of type I IFN and IRF-1, the latter playing a crucial role in late time points of VSV infection in the brain.</p></div>", "links"=>[], "tags"=>["Infectious diseases", "Infectious disease control", "Viral diseases", "factor-1", "protects", "neurotropic", "vesicular", "stomatitis", "inhibition", "viral", "replication"], "article_id"=>977773, "categories"=>["Medicine"], "users"=>["Sharmila Nair", "Kristin Michaelsen-Preusse", "Katja Finsterbusch", "Sabine Stegemann-Koniszewski", "Dunja Bruder", "Martina Grashoff", "Martin Korte", "Mario Köster", "Ulrich Kalinke", "Hansjörg Hauser", "Andrea Kröger"], "doi"=>["https://dx.doi.org/10.1371/journal.ppat.1003999.s001", "https://dx.doi.org/10.1371/journal.ppat.1003999.s002", "https://dx.doi.org/10.1371/journal.ppat.1003999.s003"], "stats"=>{"downloads"=>0, "page_views"=>14, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Interferon_Regulatory_Factor_1_Protects_from_Fatal_Neurotropic_Infection_with_Vesicular_Stomatitis_Virus_by_Specific_Inhibition_of_Viral_Replication_in_Neurons_/977773", "title"=>"Interferon Regulatory Factor-1 Protects from Fatal Neurotropic Infection with Vesicular Stomatitis Virus by Specific Inhibition of Viral Replication in Neurons", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2014-03-27 04:25:00"}
  • {"files"=>["https://ndownloader.figshare.com/files/1439504"], "description"=>"<p>Mice were infected intranasally with 5×10<sup>6</sup> pfu of VSV. A, IRF-1<sup>+/−</sup>Mx2Luc and IRF-1<sup>−/−</sup>Mx2Luc transgenic mice were subjected to whole body imaging. Mice were imaged before treatment (0 h) and over time as indicated. Images from a representative mouse are shown. The rainbow scale indicates the number of photons measured per second per cm<sup>2</sup> per steradian (sr). B, Serum was collected from WT and IRF-1<sup>−/−</sup> mice at different time points post infection. IFN-α protein level was determined by ELISA. Data represents mean with SEM of 5–6 mice in each group per time point. Asterisks indicate statistical significance calculated by Mann-Whitney test, ** p<0.005</p>", "links"=>[], "tags"=>["Infectious diseases", "Infectious disease control", "Viral diseases", "dispensable", "ifn", "vsv"], "article_id"=>977758, "categories"=>["Medicine"], "users"=>["Sharmila Nair", "Kristin Michaelsen-Preusse", "Katja Finsterbusch", "Sabine Stegemann-Koniszewski", "Dunja Bruder", "Martina Grashoff", "Martin Korte", "Mario Köster", "Ulrich Kalinke", "Hansjörg Hauser", "Andrea Kröger"], "doi"=>"https://dx.doi.org/10.1371/journal.ppat.1003999.g002", "stats"=>{"downloads"=>0, "page_views"=>23, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_IRF_1_is_dispensable_for_type_I_IFN_response_in_VSV_infections_/977758", "title"=>"IRF-1 is dispensable for type I IFN response in VSV infections.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-03-27 04:25:00"}
  • {"files"=>["https://ndownloader.figshare.com/files/1439514"], "description"=>"<p>WT mice were infected intranasally with 5×10<sup>6</sup> pfu of VSV. Expression level of IRF-1 in the lung and different brain parts were determined by real-time RT-PCR. Asterisks indicate statistical significance calculated by Mann-Whitney test, ** p<0.005.</p>", "links"=>[], "tags"=>["Infectious diseases", "Infectious disease control", "Viral diseases", "induced", "states", "vsv"], "article_id"=>977768, "categories"=>["Medicine"], "users"=>["Sharmila Nair", "Kristin Michaelsen-Preusse", "Katja Finsterbusch", "Sabine Stegemann-Koniszewski", "Dunja Bruder", "Martina Grashoff", "Martin Korte", "Mario Köster", "Ulrich Kalinke", "Hansjörg Hauser", "Andrea Kröger"], "doi"=>"https://dx.doi.org/10.1371/journal.ppat.1003999.g006", "stats"=>{"downloads"=>0, "page_views"=>6, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_IRF_1_is_induced_at_later_states_during_VSV_infection_in_the_brain_/977768", "title"=>"IRF-1 is induced at later states during VSV infection in the brain.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-03-27 04:25:00"}
  • {"files"=>["https://ndownloader.figshare.com/files/1439512"], "description"=>"<p>Mice were infected intranasally with 5×10<sup>6</sup> pfu of VSV or VSV-eGFP. A, Expression level of IFN-β in different brain parts was determined by real-time RT-PCR, A, IFN-β. B, Expression level of Mx2, Rsad2 USP-18 and IFIT-2 in the cerebrum was determined by real-time RT-PCR. Data represents mean with SEM of 3–7 mice in each group per time point. Asterisks indicate statistical significance calculated by Mann-Whitney test, ** p<0.005, * p<0.05. C, Representative pictures of immunohistological analysis of VSV-eGFP and IFIT-2 protein 6 days post infection in the cerebrum of IRF-1<sup>−/−</sup> and WT mice. IFIT2 (red), DAPI (blue), VSV-eGFP (green). Scale bar is 50 μm.</p>", "links"=>[], "tags"=>["Infectious diseases", "Infectious disease control", "Viral diseases", "isg", "mrna", "neurotropic", "vsv"], "article_id"=>977766, "categories"=>["Medicine"], "users"=>["Sharmila Nair", "Kristin Michaelsen-Preusse", "Katja Finsterbusch", "Sabine Stegemann-Koniszewski", "Dunja Bruder", "Martina Grashoff", "Martin Korte", "Mario Köster", "Ulrich Kalinke", "Hansjörg Hauser", "Andrea Kröger"], "doi"=>"https://dx.doi.org/10.1371/journal.ppat.1003999.g005", "stats"=>{"downloads"=>8, "page_views"=>83, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_IFN_946_and_ISG_mRNA_expression_in_neurotropic_VSV_infection_/977766", "title"=>"IFN-β and ISG mRNA expression in neurotropic VSV infection.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-03-27 04:25:00"}
  • {"files"=>["https://ndownloader.figshare.com/files/1439509"], "description"=>"<p>WT and IRF-1<sup>−/−</sup> mice infected intranasally with 5×10<sup>6</sup> pfu of VSV or VSV-eGFP and viral burden was quantitated by plaque assay from A, peripheral organs- liver, spleen, lung and B, brain parts- olfactory bulb, cerebrum, cerebellum and brain stem. Data are representative of at least two independent experiments. Asterisks indicate statistical significance calculated by Mann-Whitney test, * p<0.05. C/D, Representative pictures of immunohistological analysis of VSV-eGFP protein in the brain stem and different parts of the cerebrum in IRF-1<sup>−/−</sup> mice (VSV-eGFP (green), DAPI (blue). C, 2 days post infection, D, 6 days post infection. Scale bar 100 μm</p>", "links"=>[], "tags"=>["Infectious diseases", "Infectious disease control", "Viral diseases", "mediated", "antiviral", "viral", "replication", "stages"], "article_id"=>977763, "categories"=>["Medicine"], "users"=>["Sharmila Nair", "Kristin Michaelsen-Preusse", "Katja Finsterbusch", "Sabine Stegemann-Koniszewski", "Dunja Bruder", "Martina Grashoff", "Martin Korte", "Mario Köster", "Ulrich Kalinke", "Hansjörg Hauser", "Andrea Kröger"], "doi"=>"https://dx.doi.org/10.1371/journal.ppat.1003999.g004", "stats"=>{"downloads"=>0, "page_views"=>12, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_IRF_1_mediated_antiviral_effect_is_critical_for_viral_replication_during_later_stages_of_viral_replication_in_the_brain_/977763", "title"=>"IRF-1 mediated antiviral effect is critical for viral replication during later stages of viral replication in the brain.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-03-27 04:25:00"}
  • {"files"=>["https://ndownloader.figshare.com/files/1439517"], "description"=>"<p>WT and IRF-1<sup>−/−</sup> mice were infected intranasally with 5×10<sup>6</sup> pfu VSV. A, B, Leukocytes were isolated from brains of WT and IRF-1<sup>−/−</sup> 6 days post infection by Percoll gradient centrifugation, stained for CD11b and CD45, and analyzed by flow cytometry, A, Representative flow cytometry profiles of CD11b and CD45 staining of brain leukocytes from WT and IRF-1<sup>−/−</sup> mice are shown, B, Total cell numbers for infiltrating monocytes (mono) (CD45Hi CD11b+), microglia (mg) (CD45Lo CD11b+) CD8<sup>+</sup> T cells (CD8<sup>+</sup>) and NK cells (DX5<sup>+</sup>CD3<sup>−</sup>) were evaluated. C, Expression levels of IL-1β and TNF-α mRNA were recorded by real-time RT-PCR from the cerebrum of WT and IRF-1<sup>−/−</sup> mice. Asterisks indicate statistical significance calculated by Mann- Whitney test, ** p<0.005, * p<0.05.</p>", "links"=>[], "tags"=>["Infectious diseases", "Infectious disease control", "Viral diseases", "irf-1", "leads", "inflammatory"], "article_id"=>977771, "categories"=>["Medicine"], "users"=>["Sharmila Nair", "Kristin Michaelsen-Preusse", "Katja Finsterbusch", "Sabine Stegemann-Koniszewski", "Dunja Bruder", "Martina Grashoff", "Martin Korte", "Mario Köster", "Ulrich Kalinke", "Hansjörg Hauser", "Andrea Kröger"], "doi"=>"https://dx.doi.org/10.1371/journal.ppat.1003999.g008", "stats"=>{"downloads"=>1, "page_views"=>8, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_The_absence_of_IRF_1_leads_to_an_inflammatory_response_in_the_brain_/977771", "title"=>"The absence of IRF-1 leads to an inflammatory response in the brain.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-03-27 04:25:00"}
  • {"files"=>["https://ndownloader.figshare.com/files/1439502"], "description"=>"<p>A, Survival analysis of WT (n = 12), IRF-1<sup>−/−</sup> (n = 10) and IFNAR<sup>−/−</sup> (n = 5) mice. 8-10-week-old mice were infected intranasally with 5×10<sup>6</sup> (WT, IRF-1<sup>−/−</sup>) or 10<sup>2</sup> (IFNAR<sup>−/−</sup>) pfu VSV and mortality was observed for 15 days. B, Survival curves of WT (n = 5) and IRF-1<sup>−/−</sup> (n = 6) mice after intravenous infection with 5×10<sup>6</sup> pfu VSV. Data are representative of at least two independent experiments. Survival differences were tested for statistical significance by the log-rank test.</p>", "links"=>[], "tags"=>["Infectious diseases", "Infectious disease control", "Viral diseases", "protects", "mice", "lethal", "intranasal", "vsv"], "article_id"=>977756, "categories"=>["Medicine"], "users"=>["Sharmila Nair", "Kristin Michaelsen-Preusse", "Katja Finsterbusch", "Sabine Stegemann-Koniszewski", "Dunja Bruder", "Martina Grashoff", "Martin Korte", "Mario Köster", "Ulrich Kalinke", "Hansjörg Hauser", "Andrea Kröger"], "doi"=>"https://dx.doi.org/10.1371/journal.ppat.1003999.g001", "stats"=>{"downloads"=>2, "page_views"=>97, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_IRF_1_protects_mice_from_lethal_intranasal_VSV_infection_/977756", "title"=>"IRF-1 protects mice from lethal intranasal VSV infection.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-03-27 04:25:00"}
  • {"files"=>["https://ndownloader.figshare.com/files/1439516"], "description"=>"<p>Primary hippocampal neurons cultured from WT and IRF-1<sup>−/−</sup> mice. A, Cultures were infected with 0.01 MOI VSV-eGFP and stained with GFAP (astrocytes) and NeuN (neurons) by immunofluorescence assay. Scale bar 50 μm. B, Cultures were infected with 0.001 MOI VSV and viral replication from 24–72 hours were measured by plaque assay. Asterisks indicate statistical significance calculated by Mann-Whitney test, ** p<0.005. C, IRF-1<sup>−/−</sup> mice was infected intranasally with 5×10<sup>6</sup> pfu VSV. Representative pictures of immunohistological analysis of VSV-eGFP (green), DAPI (blue) in neurons (NeuN: red), astrocytes (GFAP: red) of the cerebrum and microglia (IBA: red) from the brain stem 6 days post infection. Scale bar 50 μm.</p>", "links"=>[], "tags"=>["Infectious diseases", "Infectious disease control", "Viral diseases", "inhibits", "viral", "replication"], "article_id"=>977770, "categories"=>["Medicine"], "users"=>["Sharmila Nair", "Kristin Michaelsen-Preusse", "Katja Finsterbusch", "Sabine Stegemann-Koniszewski", "Dunja Bruder", "Martina Grashoff", "Martin Korte", "Mario Köster", "Ulrich Kalinke", "Hansjörg Hauser", "Andrea Kröger"], "doi"=>"https://dx.doi.org/10.1371/journal.ppat.1003999.g007", "stats"=>{"downloads"=>1, "page_views"=>24, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_IRF_1_inhibits_viral_replication_in_primary_neurons_/977770", "title"=>"IRF-1 inhibits viral replication in primary neurons.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-03-27 04:25:00"}

PMC Usage Stats | Further Information

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Relative Metric

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