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 CD3ɛ 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.
authors: Division of Biologics Review and Research-III, Office of Biotechnology, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD 20993, USA.
authors: Derek Dc
authors: DD
authors: Ireland
authors: Division of Biologics Review and Research-III, Office of Biotechnology, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD 20993, USA.
authors: Cecilia
authors: C
authors: Tami
authors: Division of Biologics Review and Research-III, Office of Biotechnology, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD 20993, USA.
authors: Joao
authors: J
authors: Pedras-Vasconcelos
authors: Division of Biologics Review and Research-III, Office of Biotechnology, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD 20993, USA.
authors: Daniela
authors: D
authors: Verthelyi
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis; D001117:Arenaviridae Infections / Q000276:immunology* / Q000473:pathology / Q000821:virology*; D018050:Arenavirus / Q000502:physiology*; D001253:Astrocytes / Q000473:pathology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002490:Central Nervous System / Q000473:pathology / Q000821:virology; D005911:Gliosis / Q000473:pathology; D008590:Meningoencephalitis / Q000276:immunology* / Q000473:pathology / Q000821:virology*; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017628:Microglia / Q000473:pathology; D009410:Nerve Degeneration / Q000473:pathology; D009474:Neurons / Q000473:pathology; D011689:Purkinje Cells / Q000473:pathology; D013601:T-Lymphocytes / Q000276:immunology