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Title: CD4 and CD8 T cells mediate distinct lethal meningoencephalitis in mice challenged with Tacaribe arenavirus

Abstract

Neonates are at increased risk of viral encephalopathies that can result in neurological dysfunction, seizures, permanent disability and even death. The neurological damage results from the combined effect of the virus and the immune response it elicits, thus finding tools to facilitate viral clearance from central nervous system (CNS) while minimizing neuron damage remains a critical challenge. Neonatal mice inoculated intraperitoneally with Tacaribe virus (TCRV) develop seizures, hindlimb paralysis and death within 15 days of inoculation. TCRV localizes to the CNS within days of challenge, primarily infecting astrocytes in the cerebellum and brain stem. We show that infection leads to inflammation, T cell and monocyte infiltration into the cerebellar parenchyma, apoptosis of astrocytes, neuronal degeneration and loss of Purkinje cells. Infiltrating antigen-specific T cells fail to clear the virus but drive the disease, as T-cell-deficient CD3ϵ KO mice survive TCRV infection with minimal inflammation or clinical manifestations despite no difference in CNS viral loads in comparison with T-cell sufficient mice. CD8+ T cells drive the pathology, which even in the absence of CD4+ T-cell help, infiltrate the parenchyma and mediate the apoptotic loss of cerebellar astrocytes, neurodegeneration and loss of Purkinje cells resulting in loss of balance, paralysis and death.more » CD4+ T cells are also pathogenic inducing gliosis and inflammation in the cerebellum and cerebrum that are associated with wasting and death several weeks after CD4+ T-cell transfer. These data demonstrate distinct pathogenic effects of CD4+ and CD8+ T cells and identify them as possible therapeutic targets.« less

Authors:
 [1];  [1];  [1]; ORCiD logo [1]
+ Show Author Affiliations
  1. U.S. Food and Drug Administration (FDA), Silver Spring, MD (United States). Division of Biologics Review and Research-III, Office of Biotechnology, Center for Drug Evaluation and Research
Publication Date:
Research Org.:
Oak Ridge Institute for Science and Education (ORISE), Oak Ridge, TN (United States)
Sponsoring Org.:
USDOE Office of Science (SC); US Food and Drug Administration (FDA)
OSTI Identifier:
1623747
Grant/Contract Number:  
SC0014664
Resource Type:
Accepted Manuscript
Journal Name:
Cellular & Molecular Immunology
Additional Journal Information:
Journal Volume: 14; Journal Issue: 1; Journal ID: ISSN 1672-7681
Publisher:
Springer Nature
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; immunology; CD4 T cells; CD8 T cells; encephalitis; Purkinje cells; virus

Citation Formats

Ireland, Derek DC, Tami, Cecilia, Pedras-Vasconcelos, Joao, and Verthelyi, Daniela. CD4 and CD8 T cells mediate distinct lethal meningoencephalitis in mice challenged with Tacaribe arenavirus. United States: N. p., 2016. Web. doi:10.1038/cmi.2016.41.
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Ireland, Derek DC, Tami, Cecilia, Pedras-Vasconcelos, Joao, & Verthelyi, Daniela. CD4 and CD8 T cells mediate distinct lethal meningoencephalitis in mice challenged with Tacaribe arenavirus. United States. https://doi.org/10.1038/cmi.2016.41
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Ireland, Derek DC, Tami, Cecilia, Pedras-Vasconcelos, Joao, and Verthelyi, Daniela. Mon . "CD4 and CD8 T cells mediate distinct lethal meningoencephalitis in mice challenged with Tacaribe arenavirus". United States. https://doi.org/10.1038/cmi.2016.41. https://www.osti.gov/servlets/purl/1623747.
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@article{osti_1623747,
title = {CD4 and CD8 T cells mediate distinct lethal meningoencephalitis in mice challenged with Tacaribe arenavirus},
author = {Ireland, Derek DC and Tami, Cecilia and Pedras-Vasconcelos, Joao and Verthelyi, Daniela},
abstractNote = {Neonates are at increased risk of viral encephalopathies that can result in neurological dysfunction, seizures, permanent disability and even death. The neurological damage results from the combined effect of the virus and the immune response it elicits, thus finding tools to facilitate viral clearance from central nervous system (CNS) while minimizing neuron damage remains a critical challenge. Neonatal mice inoculated intraperitoneally with Tacaribe virus (TCRV) develop seizures, hindlimb paralysis and death within 15 days of inoculation. TCRV localizes to the CNS within days of challenge, primarily infecting astrocytes in the cerebellum and brain stem. We show that infection leads to inflammation, T cell and monocyte infiltration into the cerebellar parenchyma, apoptosis of astrocytes, neuronal degeneration and loss of Purkinje cells. Infiltrating antigen-specific T cells fail to clear the virus but drive the disease, as T-cell-deficient CD3ϵ KO mice survive TCRV infection with minimal inflammation or clinical manifestations despite no difference in CNS viral loads in comparison with T-cell sufficient mice. CD8+ T cells drive the pathology, which even in the absence of CD4+ T-cell help, infiltrate the parenchyma and mediate the apoptotic loss of cerebellar astrocytes, neurodegeneration and loss of Purkinje cells resulting in loss of balance, paralysis and death. CD4+ T cells are also pathogenic inducing gliosis and inflammation in the cerebellum and cerebrum that are associated with wasting and death several weeks after CD4+ T-cell transfer. These data demonstrate distinct pathogenic effects of CD4+ and CD8+ T cells and identify them as possible therapeutic targets.},
doi = {10.1038/cmi.2016.41},
journal = {Cellular & Molecular Immunology},
number = 1,
volume = 14,
place = {United States},
year = {Mon Aug 29 00:00:00 EDT 2016},
month = {Mon Aug 29 00:00:00 EDT 2016}
}
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Journal Article:
Free Publicly Available Full Text
Publisher's Version of Record
https://doi.org/10.1038/cmi.2016.41
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Figures / Tables:

Figure 1 Figure 1: TCRV infection results in CNS inflammation, apoptosis and neurodegeneration. (a) Survival of C57BL/6 (B6 WT) mice infected with 2000 x TCID50 TCRV, i.p. (b) Relative quantification of gene expression in the CNS of B6 WT mice at 10 dpi: (i) chemokines, (ii) antigen presentation, (iii) cytokines and (iv)more » T-cell-related genes. Gene expression was normalized using GAPDH and expressed as fold change in gene expression relative to age-matched uninfected controls (log2 scale; n=6 mice per group). (c) Apoptosis in the hindbrain of B6 WT animals at 10 dpi (right) as detected by the TUNEL assay (coronal sections). (i) Whole section image (406-Diamidino-2-Pheylindole (DAPI)), with box indicating location of imaging in (ii) and (iii). (ii) Uninfected, age-matched cerebellum at P13. (iii) TCRV-infected WT mice at 10 dpi (age=P13). TUNEL-positive cells (green) co-stained for neurons (anti-NeuN), astrocytes (anti-GFAP), microglia (anti-Iba-1) or CD45+ infiltrating cells (all shown in red). Arrows in (ciii) indicate GFAP+TUNEL+ cells or CD45+TUNEL+ cells, respectively. Scale bars: (ii) and left column of (iii)=200 μm; right column of (iii)=100 μm. Inset, GFAP+TUNEL+ cells, scale bar=50 μm. (d) Hematoxylin and eosin of uninfected and TCRV-infected CNS collected at 10 dpi (sagittal sections). Scale bar=100 μm. (e) TUNEL (green) and Purkinje cells (α-Fox2, red) in the cerebellum (coronal sections; scale bar=400 μm) of age-matched uninfected (left column) and TCRV-infected mice (10 dpi). (f) Fluor-Jade B stain for degenerative neurons (green). (g) Quantification of TUNEL, Fluoro-Jade B and Fox2+ cells. The mean number of cells/mm2 counted in at least five fields of view per section from at least two mice. Statistical significance denoted as *P< 0.05; **P < 0.01. Abbreviations: CNS, central nervous system; TCRV, Tacaribe virus; WT, wild type; TUNEL, terminal deoxynucleotidyl transferase dUTP nick end labeling.« less
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