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

Pedras-Vasconcelos, João; Puig, Montserrat; Sauder, Christian; Wolbert, Candie; Ovanesov, Mikhail V.; Goucher, David; Verthelyi, Daniela

doi:10.4049/jimmunol.180.12.8231

Cited by 22 publications

(25 citation statements)

References 44 publications

(62 reference statements)

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“…The dissimilarity in the neuroinflammatory response elicited by TLR7 and TLR9 signaling may explain some of the differences observed in the ability of TLR7 and TLR9 agonists to provide protection in the CNS during viral infection and in the toxic nature of CpG-ODNs in the CNS. 17,18 This in vivo result differs substantially from in vitro stimulation of these receptors, which elicited similar cytokine responses in astrocytes, microglia, and B cells. 21,24 The difference in the proinflammatory responses between TLR7 and TLR9 agonist stimulation were due, at least in part, to their ability to activate cells of the choroid plexus to produce proinflammatory cytokines, such as TNF and IL-6.…”

Section: Discussionmentioning

confidence: 90%

“…For example, peripheral administration of TLR9 agonists protected neonatal mice from a lethal challenge with neurotropic Tacaribe arenavirus, whereas TLR7 agonists did not. 17,18 IntraceSupported in part by the Intramural Research Program of the NIH and in part by National Center for Research Resources grant IP20RR020159. rebroventricular (ICV) inoculation of TLR9 agonists was lethal in newborn mice, but ICV inoculation of TLR7 agonists was not.…”

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confidence: 99%

“…rebroventricular (ICV) inoculation of TLR9 agonists was lethal in newborn mice, but ICV inoculation of TLR7 agonists was not. [17][18][19] Understanding differences in the neuroinflammatory capabilities of TLR7 and TLR9 agonists will be important for using the agonists in the treatment of neurologic diseases, including neurovirulent viral infections. This is particularly true in the developing brain, where viral infection can lead to severe neurologic damage or death.…”

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TLR7 and TLR9 Trigger Distinct Neuroinflammatory Responses in the CNS

Butchi

Woods

et al. 2011

The American Journal of Pathology

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Toll-like receptors (TLRs) 7 and 9 recognize nucleic acid determinants from viruses and bacteria and elicit the production of type I interferons and proinflammatory cytokines. TLR7 and TLR9 are similar regarding localization and signal transduction mechanisms. However, stimulation of these receptors has differing effects in modulating viral pathogenesis and in direct toxicity in the central nervous system (CNS). In the present study, we examined the potential of the TLR7 agonist imiquimod and the TLR9 agonist cytosine-phosphateguanosine oligodeoxynucleotide (CpG-ODN) to induce neuroinflammation after intracerebroventricular inoculation. CpG-ODN induced a more robust inflammatory response than did imiquimod after inoculation into the CNS, with higher levels of several proinflammatory cytokines and chemokines. The increase in cytokines and chemokines correlated with breakdown of the bloodcerebrospinal fluid barrier and recruitment of peripheral cells to the CNS in CpG-ODN-inoculated mice. In contrast, TLR7 agonists induced a strong interferon ␤ response in the CNS but only low levels of other cytokines. The difference in response to these agonists was not due to differences in distribution or longevity of the agonists but rather was correlated with cytokine production by choroid plexus cells. These results indicate that despite the high similarity of TLR7 and TLR9 in binding nucleic acids and inducing similar downstream signaling, the neuroinflammation response induced by these receptors differs dramatically due, at least in part, to activation of cells in the choroid plexus.

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Section: Discussionmentioning

confidence: 90%

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confidence: 99%

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confidence: 99%

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TLR7 and TLR9 Trigger Distinct Neuroinflammatory Responses in the CNS

Butchi

Woods

et al. 2011

The American Journal of Pathology

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“…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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“…Agonists of both TLR7 and TLR9 are also being investigated for the potential use in treating CNS-related diseases (Butchi et al, 2008; El Andaloussi A. et al, 2006; Pedras-Vasconcelos et al, 2006; Pedras-Vasconcelos et al, 2008; Prins et al, 2006). However, there appears to be some differences in the CNS response to activation of these receptors.…”

Section: Introductionmentioning

confidence: 99%

Interactions between TLR7 and TLR9 agonists and receptors regulate innate immune responses by astrocytes and microglia

Butchi

Peterson

2009

Glia

104

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Toll like receptors 7 (TLR7) and 9 (TLR9) are important mediators of innate immune responses. Both receptors are located in endosomal compartments, recognize nucleic acids and signal via Myeloid differentiation factor 88 (MyD88). In the current study, we analyzed TLR7 and TLR9 induced activation of astrocytes and microglia, two cell types that contribute to innate immune responses in the CNS. TLR7 and TLR9 agonists induced similar cytokine profiles in each cell types. However, there were notable differences in the cytokine profile between astrocytes and microglia, including the production of the anti-inflammatory cytokine IL-10 and anti-apoptotic cytokines G-CSF and IL-9 by microglia but not astrocytes. Costimulation studies demonstrated that the TLR7 agonist, imiquimod, could inhibit TLR9 agonist-induced innate immune responses, in both cell types, in a concentration dependent manner. Surprisingly, this inhibition was not mediated by TLR7, as deficiency in TLR7 did not alter suppression of the TLR9 agonist-induced responses. The suppression of innate immune responses was also not due to an inhibition of TLR9 agonist uptake. This suggested that imiquimod suppression may be a direct effect, possibly by blocking CpG-ODN binding and/or signaling with TLR9, thus limiting cell activation. An antagonistic relationship was also observed between the two receptors in microglia, with TLR7 deficiency resulting in enhanced cytokine responses to CpG-ODN stimulation. Thus, both TLR7 and its agonist can have inhibitory effects on TLR9-induced cytokine responses in glial cells.

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

Cited by 22 publications

References 44 publications

TLR7 and TLR9 Trigger Distinct Neuroinflammatory Responses in the CNS

TLR7 and TLR9 Trigger Distinct Neuroinflammatory Responses in the CNS

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

Interactions between TLR7 and TLR9 agonists and receptors regulate innate immune responses by astrocytes and microglia

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