Infection with viruses of the Tacaribe group in thymectomized mice

Parodi, A. S.; Schmuñis, Gabriel A.; Weissenbacher, Mercedes

doi:10.1007/bf01898754

Cited by 6 publications

(6 citation statements)

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“…1, F and G) (31). Despite the paucity of infiltrating cells, early observations that thymectomized and nude nu/nu mice survive TCRV infection suggested a role for T cells (8,10,11) that was confirmed in this study using RAG Ϫ/Ϫ mice (Fig. 2).…”

Section: Discussionsupporting

confidence: 77%

“…T cells are known to cross the blood-brain barrier (BBB) during viral infections and pioneering studies on TCRV had shown that thymectomized mice survive an infectious challenge, suggesting that T cells play an important role in disease pathogenesis (8,11). Despite this, H&E staining of cerebellum sections showed no significant cellular infiltration even in areas that had high levels of viral Ag (Fig.…”

Section: Tcrv Induces Cns Cells To Produce Rantes and Ifn-␣ But Not Imentioning

confidence: 99%

“…In mice, TCRV causes a lethal meningoencephalitis in neonatal mice that is characterized by diminished activity, weight loss, flaccid progressive paralysis, and death 1-2 wk after infection depending on the strain, dose, and route of inoculation (8,9). Previous studies had shown increased survival in challenged mice that lacked T cells (8,10,11). More recently, our group showed that systemic administration of immunostimulatory oligonucleotides containing a CpG motif (CpG oligodeoxynucleotide (ODN)) at the time of infection accelerated Ab production to the virus and reduced levels of IFN-␥ and TNF-␣ in the CNS, but only marginally improved survival (30 -50%) (9).…”

mentioning

confidence: 99%

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Immunotherapy with CpG Oligonucleotides and Antibodies to TNF-α Rescues Neonatal Mice from Lethal Arenavirus-Induced Meningoencephalitis

Pedras-Vasconcelos

Puig

Sauder

et al. 2008

The Journal of Immunology

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Viral encephalitides are life-threatening diseases in neonates partly due to the irreversible damage inflammation causes to the CNS. This study explored the role of proinflammatory cytokines in the balance between controlling viral replication and eliciting pathologic immune responses in nonlytic viral encephalitis. We show that neonatal mice challenged with arenavirus Tacaribe (TCRV) develop a meningoencephalitis characterized by high IFN-γ and TNF-α levels and mild T cell infiltration. Neutralization of the TNF-α using mAb was associated with lower chemokine expression, reduced T cell infiltration, and lower levels of IFN-γ, and TNF-α in the CNS and led to 100% survival. Moreover, treatment with Abs to TNF-α improved mobility and increased survival even after the mice developed bilateral hind limb paralysis. Of note, animals treated with anti-TNF-α Abs alone did not clear the virus despite generating Abs to TCRV. Direct activation of the innate immune response using CpG oligodeoxynucleotides in combination with anti-TNF-α Abs resulted in 100% survival and complete viral clearance. To our knowledge, this is the first demonstration of the use of innate immune modulators plus Abs to TNF-α as therapeutics for a lethal neurotropic viral infection.

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Section: Discussionsupporting

confidence: 77%

Section: Tcrv Induces Cns Cells To Produce Rantes and Ifn-␣ But Not Imentioning

confidence: 99%

mentioning

confidence: 99%

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Immunotherapy with CpG Oligonucleotides and Antibodies to TNF-α Rescues Neonatal Mice from Lethal Arenavirus-Induced Meningoencephalitis

Pedras-Vasconcelos

Puig

Sauder

et al. 2008

The Journal of Immunology

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“…14 To explore directly the role of the immune response in disease we first assessed whether the immune cells infiltrated the CNS of TCRV-infected mice. Flow cytometry of single-cell suspension from the CNS at 10 dpi showed that 20% of microglia (CD45lo; Figure 2ai) in the CNS have increased expression of MHC class 2 ((H2-Eb1, Class 2; Figure 2ai), compared with <1% in age-matched uninfected controls.…”

Section: Resultsmentioning

confidence: 99%

“…6, 11 This indicates that T cells play an important role in pathogenesis although these cells cannot be infected by the virus. 11, 13, 14, 15 Currently the role of T cells in the CNS is an area of intense study, but their precise roles in the context of viral encephalopathy are not fully understood. Recent studies proposing the use of adoptive transfer with antiviral T cells as a possible treatment to clear microglia persistently infected with Old World Clade arenavirus lymphocytic choriomeningitis virus (LCMV) underscore the need to understand the role of T cells in viral meningoencephalitis.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2016

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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.

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Different histopathological response to Arenovirus infection in thymectomized mice

Besuschio

Weissenbacher

Schmuñis

1973

Archiv f Virusforschung

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Infection with viruses of the Tacaribe group in thymectomized mice

Cited by 6 publications

References 0 publications

Immunotherapy with CpG Oligonucleotides and Antibodies to TNF-α Rescues Neonatal Mice from Lethal Arenavirus-Induced Meningoencephalitis

Immunotherapy with CpG Oligonucleotides and Antibodies to TNF-α Rescues Neonatal Mice from Lethal Arenavirus-Induced Meningoencephalitis

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

Different histopathological response to Arenovirus infection in thymectomized mice

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