Loss of mandibular lymph node integrity is associated with an increase in sensitivity to HSV-1 infection in CD118-deficient mice.
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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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
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
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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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
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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TL;DR: Since IFN-α/β are very efficiently generated in response to viral and bacterial infections, these molecules may be among the signals that the immune system uses to prevent activated T cell death during infections.
Abstract: Antigen injection into animals causes antigen-specific T cells to become activated and, rapidly thereafter, die. This antigen-induced death is inhibited by inflammation. To find out how inflammation has this effect, various cytokines were tested for their ability to interfere with the rapid death of activated T cells. T cells were activated in vivo, isolated, and cultured with the test reagents. Two groups of cytokines were active, members of the interleukin 2 family and the interferons (IFNs) α and β. This activity of IFN-α/β has not been described previously. It was due to direct effects of the IFNs on the T cells and was not mediated by induction of a second cytokine such as interleukin 15. IFN-γ did not slow the death of activated T cells, and therefore the activity of IFN-α/β was not mediated only by activation of Stat 1, a protein that is affected by both classes of IFN. IFN-α/β did not raise the levels of Bcl-2 or Bcl-XL in T cells. Therefore, their activity was distinct from that of members of the interleukin 2 family or CD28 engagement. Since IFN-α/β are very efficiently generated in response to viral and bacterial infections, these molecules may be among the signals that the immune system uses to prevent activated T cell death during infections.
791 citations
"Loss of mandibular lymph node integ..." refers background in this paper
...Type I IFNs provide direct support of the host adaptive immune system at the level of T cells (22, 23) and DCs (24 –26) and, therefore, antagonize the action of HSV-1-encoded proteins....
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TL;DR: Two unrelated infants homozygous with respect to mutated STAT1 alleles are reported, both infants suffered from mycobacterial disease, but unlike individuals with IFN-γR deficiency, both died of viral disease.
Abstract: The receptors for interferon-alpha/beta (IFN-alpha/beta) and IFN-gamma activate components of the Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling pathway, leading to the formation of at least two transcription factor complexes. STAT1 interacts with STAT2 and p48/IRF-9 to form the transcription factor IFN-stimulated gene factor 3 (ISGF3). STAT1 dimers form gamma-activated factor (GAF). ISGF3 is induced mainly by IFN-alpha/beta, and GAF by IFN-gamma, although both factors can be activated by both types of IFN. Individuals with mutations in either chain of the IFN-gamma receptor (IFN-gammaR) are susceptible to infection with mycobacteria. A heterozygous STAT1 mutation that impairs GAF but not ISGF3 activation has been found in other individuals with mycobacterial disease. No individuals with deleterious mutations in the IFN-alpha/beta signaling pathway have been described. We report here two unrelated infants homozygous with respect to mutated STAT1 alleles. Neither IFN-alpha/beta nor IFN-gamma activated STAT1-containing transcription factors. Like individuals with IFN-gammaR deficiency, both infants suffered from mycobacterial disease, but unlike individuals with IFN-gammaR deficiency, both died of viral disease. Viral multiplication was not inhibited by recombinant IFN-alpha/beta in cell lines from the two individuals. Inherited impairment of the STAT1-dependent response to human IFN-alpha/beta thus results in susceptibility to viral disease.
727 citations
"Loss of mandibular lymph node integ..." refers background in this paper
...The absence of one of the components within the signaling cascade STAT1 increases susceptibility to viral pathogens in humans (4) and mice (5)....
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TL;DR: It is shown that ICP47 efficiently inhibits peptide transport across the ER membrane such that nascent class I molecules fail to acquire antigenic peptides.
Abstract: Cytotoxic T lymphocytes lyse target cells after T-cell-receptor-mediated recognition of class I major histocompatibility complex molecules presenting peptides Antigenic peptides are generated in the cytoplasm by proteasomes and translocated into the lumen of the endoplasmic reticulum (ER) by peptide transporters (TAP) Herpes simplex virus (HSV) expresses a cytoplasmic protein, ICP47, which seems to interfere with such immune surveillance by mediating retention of 'empty' class I molecules in the ER By expressing ICP47 in HeLa cells under an inducible promoter, we show that ICP47 efficiently inhibits peptide transport across the ER membrane such that nascent class I molecules fail to acquire antigenic peptides This inhibition was overcome by transfecting murine TAP Further, we demonstrate that ICP47 colocalizes and physically associates with TAP within the cell Inhibition of peptide translocation by a viral protein indicates a previously undocumented potential mechanism for viral immune evasion
616 citations
TL;DR: It is shown that IFN-αβ can provide the third signal directly to CD8 T cells via a STAT4-dependent pathway to stimulate survival, development of cytolytic function, and production of IFn-γ.
Abstract: In this study, we show that IFN-αβ can have a direct role in linking innate and adaptive responses by providing the “third signal” needed by naive CD8 T cells responding to Ag and costimulatory ligands. Stimulation of CD8 T cells in the absence of a third signal leads to proliferation, but clonal expansion is limited by poor survival and effector functions do not develop. We show that IFN-αβ can provide the third signal directly to CD8 T cells via a STAT4-dependent pathway to stimulate survival, development of cytolytic function, and production of IFN-γ. Provision of the third signal by either IFN-αβ or IL-12 results in regulation of the expression of a number of genes, including several that encode proteins critical for effector function.
609 citations
"Loss of mandibular lymph node integ..." refers background in this paper
...Because type I IFNs have previously been reported to facilitate CD8 T cell clonal expansion in a STAT-4-dependent manner (41), the level of HSV gB-specific CD8 T cell numbers was evaluated in the MLN of WT and CD118 / mice following ocular HSV-1 infection....
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TL;DR: The results define the coordinated interactions between the cytokines IFN-αβ, IL-12, and IL-15 for activation of protective NK cell responses during viral infections, and emphasize these factors’ nonredundant functions under in vivo physiological conditions.
Abstract: NK cell cytotoxicity, IFN-γ expression, proliferation, and accumulation are rapidly induced after murine CMV infections. Under these conditions, the responses were shown to be elicited in overlapping populations. Nevertheless, there were distinct signaling molecule requirements for induction of functions within the subsets. IL-12/STAT4 was critical for NK cell IFN-γ expression, whereas IFN-αβ/STAT1 were required for induction of cytotoxicity. The accumulation/survival of proliferating NK cells was STAT4-independent but required IFN-αβ/STAT1 induction of IL-15. Taken together, the results define the coordinated interactions between the cytokines IFN-αβ, IL-12, and IL-15 for activation of protective NK cell responses during viral infections, and emphasize these factors’ nonredundant functions under in vivo physiological conditions.
607 citations