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Journal ArticleDOI

Loss of mandibular lymph node integrity is associated with an increase in sensitivity to HSV-1 infection in CD118-deficient mice.

15 Mar 2009-Journal of Immunology (NIH Public Access)-Vol. 182, Iss: 6, pp 3678-3687
TL;DR: The adoptive transfer of HSV-specific TCR transgenic CD8+ T cells into CD118−/− mice at the time of infection modestly reduced viral titers in the nervous system suggesting in addition to the generation of HSv-specific CD8 + T cells, other type I IFN-activated pathways are instrumental in controlling acute infection.
Abstract: Type I IFNs are potent antiviral cytokines that contribute to the development of the adaptive immune response. To determine the role of type I IFNs in this process in an infectious disease model, mice deficient in the type I IFN receptor (CD118(-/-)) were ocularly infected with HSV-1 and surveyed at times post infection in the nervous system and lymph node for virus and the host immune response. Virus titers were elevated in the trigeminal ganglia and brain stem with virus disseminating rapidly to the draining lymph node of CD118(-/-) mice. T cell and plasmacytoid dendritic cell infiltration into the brain stem was reduced in CD118(-/-) mice following infection, which correlated with a reduction in CXCL10 but not CXCL9 expression. In contrast, CXCL1 and CCL2 levels were up-regulated in the brainstem of CD118(-/-) mice associated with an increase in F4/80(+) macrophages. By day 5 post infection, there was a significant loss in T, NK, and plasmacytoid dendritic cell numbers in the draining lymph nodes associated with an increase in apoptotic/necrotic T cells and an appreciable lack of HSV-specific CD8(+) T cells. The adoptive transfer of HSV-specific TCR transgenic CD8(+) T cells into CD118(-/-) mice at the time of infection modestly reduced viral titers in the nervous system suggesting in addition to the generation of HSV-specific CD8(+) T cells, other type I IFN-activated pathways are instrumental in controlling acute infection.

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Citations
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Journal ArticleDOI
TL;DR: A greater understanding of the contribution of resident glial cells and infiltrating leukocytes within the CNS in response to HSV-1 invasion is necessary to identify candidate molecules as targets for therapeutic intervention to reduce unwarranted inflammation coinciding with the maintenance of the anti-viral state.

127 citations

Journal ArticleDOI
TL;DR: It is reported that TLR signaling is expendable in herpes simplex virus (HSV)-1 containment as depicted by plaque assays of knockout mice resembling wild-type controls, and an IRF-3-dependent, IRF7- and TLR-independent innate sensor responsible for HSV containment at the site of acute infection is identified.

109 citations

Journal ArticleDOI
TL;DR: This review illustrates examples of established brain barrier models, in which the specific reaction patterns of different viral families can be analyzed, and highlights the pathogen specific array of cytokines and chemokines involved in immunological responses in viral CNS infections.
Abstract: Neurotropic viruses can cause devastating central nervous system (CNS) infections, especially in young children and the elderly. The blood-brain barrier (BBB) and the blood-cerebrospinal fluid barrier (BCSFB) have been described as relevant sites of entry for specific viruses as well as for leukocytes, which are recruited during the proinflammatory response in the course of CNS infection. In this review, we illustrate examples of established brain barrier models, in which the specific reaction patterns of different viral families can be analyzed. Furthermore, we highlight the pathogen specific array of cytokines and chemokines involved in immunological responses in viral CNS infections. We discuss in detail the link between specific cytokines and chemokines and leukocyte migration profiles. The thorough understanding of the complex and interrelated inflammatory mechanisms as well as identifying universal mediators promoting CNS inflammation is essential for the development of new diagnostic and treatment strategies.

99 citations


Cites background from "Loss of mandibular lymph node integ..."

  • ...In contrast, an increase in macrophages within the CNS of IFNAR-A1 deficient mice has been observed [138]....

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Journal ArticleDOI
TL;DR: CCL2 expression driven by IFI-16 recognition of HSV-1 facilitates the recruitment of inflammatory monocytes into the cornea proper to control viral replication.

82 citations

Journal ArticleDOI
TL;DR: Using magnetic resonance imaging and type I IFN receptor–deficient mouse chimeras, it is demonstrated HSV-1 gains access to the murine brain stem and subsequently brain ependymal cells, leading to enlargement of the cerebral lateral ventricle and infection of the brain parenchyma in mice.
Abstract: HSV-1 is the leading cause of sporadic viral encephalitis, with mortality rates approaching 30% despite treatment with the antiviral drug of choice, acyclovir. Permanent neurologic deficits are common in patients that survive, but the mechanism leading to this pathology is poorly understood, impeding clinical advancements in treatment to reduce CNS morbidity. Using magnetic resonance imaging and type I IFN receptor-deficient mouse chimeras, we demonstrate HSV-1 gains access to the murine brain stem and subsequently brain ependymal cells, leading to enlargement of the cerebral lateral ventricle and infection of the brain parenchyma. A similar enlargement in the lateral ventricles is found in a subpopulation of herpes simplex encephalitic patients. Associated with encephalitis is an increase in CXCL1 and CXCL10 levels in the cerebral spinal fluid, TNF-α expression in the ependymal region, and the influx of neutrophils of encephalitic mouse brains. Reduction in lateral ventricle enlargement using anti-secretory factor peptide 16 reduces mortality significantly in HSV-1-infected mice without any effect on expression of inflammatory mediators, infiltration of leukocytes, or changes in viral titer. Microglial cells but not infiltrating leukocytes or other resident glial cells or neurons are the principal source of resistance in the CNS during the first 5 d postinfection through a Toll/IL-1R domain-containing adapter inducing IFN-β-dependent, type I IFN pathway. Our results implicate lateral ventricle enlargement as a major cause of mortality in mice and speculate such an event transpires in a subpopulation of human HSV encephalitic patients.

68 citations


Cites background from "Loss of mandibular lymph node integ..."

  • ...However, analysis of brain cortex and ependyma for cytokine and chemokine (TNF-a and CXCL10) expression by suspension array or leukocyte infiltrate (including neutrophils, macrophages, inflammatory monocytes, and NK cells) by flow cytometry revealed no significant difference in levels or cell numbers comparing peptide- to vehicle-treated mice day 7 to 8 p.i. (data not shown)....

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  • ...We speculate CXCL10 may serve as an easily accessible predictor of inflammation severity in patients with no previous history of neuroinflammatory disease....

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  • ...Likewise, HSE WT mice had detectable levels of IL-1a, CCL2, CXCL1, CXCL9, and CXCL10, with CXCL1 and CXCL10 expression significantly above that recovered in the CSF of non-HSE WT mice day 8 p.i. (Fig....

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  • ...Associated with encephalitis is an increase in CXCL1 and CXCL10 levels in the cerebral spinal fluid, TNF-a expression in the ependymal region, and the influx of neutrophils of encephalitic mouse brains....

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  • ...for CD118 mice) or the relationship between a functional type I IFN pathway and HSV-1–induced CXCL10 (34)....

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References
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Journal ArticleDOI
TL;DR: The goal is to offer a molecular and clinical perspective that will enable IFNs or their TLR agonist inducers to reach their full clinical potential.
Abstract: The family of interferon (IFN) proteins has now more than reached the potential envisioned by early discovering virologists: IFNs are not only antivirals with a spectrum of clinical effectiveness against both RNA and DNA viruses, but are also the prototypic biological response modifiers for oncology, and show effectiveness in suppressing manifestations of multiple sclerosis. Studies of IFNs have resulted in fundamental insights into cellular signalling mechanisms, gene transcription and innate and acquired immunity. Further elucidation of the multitude of IFN-induced genes, as well as drug development strategies targeting IFN production via the activation of the Toll-like receptors (TLRs), will almost certainly lead to newer and more efficacious therapeutics. Our goal is to offer a molecular and clinical perspective that will enable IFNs or their TLR agonist inducers to reach their full clinical potential.

1,069 citations


"Loss of mandibular lymph node integ..." refers background in this paper

  • ...I FN- (type I IFNs) are cytokines produced by numerous cell types typically associated with antiviral or antiproliferative characteristics and more recently, appreciated for their potential application in controlling autoimmune processes including multiple sclerosis (1, 2)....

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Journal ArticleDOI
TL;DR: It is reported here that both subclasses of DCs efficiently prime antigen-specific T cells in vivo, and direct the development of distinct T helper (Th) populations, and it is shown that interleukin 12 plays a critical role in Th1 development by CD8α+ DCs.
Abstract: Cells of the dendritic family display some unique properties that confer to them the capacity to sensitize naive T cells in vitro and in vivo. In the mouse, two subclasses of dendritic cells (DCs) have been described that differ by their CD8α expression and their localization in lymphoid organs. The physiologic function of both cell populations remains obscure. Studies conducted in vitro have suggested that CD8α+ DCs could play a role in the regulation of immune responses, whereas conventional CD8α− DCs would be more stimulatory. We report here that both subclasses of DCs efficiently prime antigen-specific T cells in vivo, and direct the development of distinct T helper (Th) populations. Antigen-pulsed CD8α+ and CD8α− DCs are separated after overnight culture in recombinant granulocyte/macrophage colony-stimulating factor and injected into the footpads of syngeneic mice. Administration of CD8α− DCs induces a Th2-type response, whereas injection of CD8α+ DCs leads to Th1 differentiation. We further show that interleukin 12 plays a critical role in Th1 development by CD8α+ DCs. These findings suggest that the nature of the DC that presents the antigen to naive T cells may dictate the class selection of the adaptative immune response.

992 citations


"Loss of mandibular lymph node integ..." refers background in this paper

  • ...Different DC subtypes are known to promote Th1 or Th2 responses (55) in which type I IFNs can contribute toward Th1 (16) or Th2 (56) development....

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Journal ArticleDOI
TL;DR: It is shown that the lack of direct CD8 T cell contact with IFN-I causes >99% reduction in their capacity to expand and generate memory cells, which is critical for the generation of effector and memory cells in response to viral infection.
Abstract: T cell expansion and memory formation are generally more effective when elicited by live organisms than by inactivated vaccines. Elucidation of the underlying mechanisms is important for vaccination and therapeutic strategies. We show that the massive expansion of antigen-specific CD8 T cells that occurs in response to viral infection is critically dependent on the direct action of type I interferons (IFN-Is) on CD8 T cells. By examining the response to infection with lymphocytic choriomeningitis virus using IFN-I receptor-deficient (IFN-IR(0)) and -sufficient CD8 T cells adoptively transferred into normal IFN-IR wild-type hosts, we show that the lack of direct CD8 T cell contact with IFN-I causes >99% reduction in their capacity to expand and generate memory cells. The diminished expansion of IFN-IR(0) CD8 T cells was not caused by a defect in proliferation but by poor survival during the antigen-driven proliferation phase. Thus, IFN-IR signaling in CD8 T cells is critical for the generation of effector and memory cells in response to viral infection.

915 citations


"Loss of mandibular lymph node integ..." refers background in this paper

  • ...In mice infected with lymphocytic choriomeningitis virus, the loss of type I IFN signaling greatly diminishes clonal expansion of CD8 T cells as a result of a defect in cell survival (64)....

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Journal ArticleDOI
01 Jun 1995-Nature
TL;DR: It is shown here that ICP47 binds to TAP and prevents peptide translocation into the endoplasmic reticulum.
Abstract: Many viruses have evolved mechanisms to avoid detection by the host immune system. Herpes simplex virus (HSV) expresses an immediate early protein, ICP47, which blocks presentation of viral peptides to MHC class I-restricted cells. The properties of the newly synthesized class I molecules in HSV-infected cells resemble those of cell lines deficient in the transporter associated with antigen processing (TAP) in that class I molecules are retained in the endoplasmic reticulum, and the heavy chain and beta 2-microglobulin subunits dissociate in detergent extracts but the complex can be stabilized by peptides. We show here that ICP47 binds to TAP and prevents peptide translocation into the endoplasmic reticulum.

854 citations

Journal ArticleDOI
TL;DR: It is shown that infection with lymphocytic choriomeningitis virus induces cross-priming by a mechanism dependent on type I interferon (IFN- α/β) and expression of IFN-α/β is identified as a mechanism for the induction of cross-Priming during virus infections.
Abstract: CD8+ T cell responses can be generated against antigens that are not expressed directly within antigen-presenting cells (APCs), through a process known as cross-priming. To initiate cross-priming, APCs must both capture extracellular antigen and receive specific activation signals. We have investigated the nature of APC activation signals associated with virus infection that stimulate cross-priming. We show that infection with lymphocytic choriomeningitis virus induces cross-priming by a mechanism dependent on type I interferon (IFN-alpha/beta). Activation of cross-priming by IFN-alpha/beta was independent of CD4+ T cell help or interaction of CD40 and CD40 ligand, and involved direct stimulation of dendritic cells. These data identify expression of IFN-alpha/beta as a mechanism for the induction of cross-priming during virus infections.

821 citations


"Loss of mandibular lymph node integ..." refers background in this paper

  • ...Type I IFNs facilitate the development of T cell immunity including TAP expression (62), which would greatly benefit the host and CD8 T cell responses through cross-priming (63)....

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