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: IL-15 is identified as a stimulatory cytokine for DCs with the potential for autocrine activity and its effects to expression of IFN-αβ are linked.
Abstract: Cytokines that are induced by infection may contribute to the initiation of immune responses through their ability to stimulate dendritic cells (DCs). In this paper, we have addressed the role of IL-15 in DC activation, investigating its expression by DCs in response to three different signals of infection and examining its ability to stimulate DCs. We report that the expression of both IL-15 and the IL-15 receptor alpha-chain are increased in splenic DCs from mice inoculated with dsRNA (poly(I:C)), LPS, or IFN-alphabeta, and in purified murine splenic DCs treated with IFN-alphabeta in vitro. Furthermore, IL-15 itself was able to activate DCs, as in vivo or in vitro exposure of splenic DCs to IL-15 resulted in an up-regulation of costimulatory molecules, markedly increased production of IFN-gamma by DC and an enhanced ability of DCs to stimulate Ag-specific CD8(+) T cell proliferation. The magnitude of all of the IL-15-induced changes in DCs was reduced in mice deficient for the IFN-alphabeta receptor, suggesting a role for IFN-alphabeta in the stimulation of DCs by IL-15. These results identify IL-15 as a stimulatory cytokine for DCs with the potential for autocrine activity and link its effects to expression of IFN-alphabeta.
426 citations
Journal Article•
TL;DR: In vivo neutralization studies of IFN-alphabeta, TNF, and IL-12 showed that each of these factors had NK and T cell-independent antiviral functions, as well as specific effects on NK cell responses.
Abstract: Murine cytomegalovirus (MCMV) infection of mice induces early cytokines. Although certain of these can directly inhibit viral replication, they also can promote defense by activating NK cells. MCMV induces IFN-alphabeta-dependent NK cell cytotoxicity and IL-12-dependent NK cell IFN-gamma production. Studies were initiated to define cytokine-mediated NK and T cell-independent antiviral defense and specific cytokine-elicited NK cell responses during MCMV infections. IFN-alphabeta, TNF, IL-12, and IFN-gamma were all shown to be induced 2 days after infection of immunocompetent mice. Infections of NK and T cell-deficient mice demonstrated that virus-induced IFN-alphabeta, TNF, and IL-12, but not IFN-gamma, were produced independently of these populations, and that IL-12 production occurred in the absence of detectable IFN-gamma. In vivo neutralization studies of IFN-alphabeta, TNF, and IL-12 showed that each of these factors had NK and T cell-independent antiviral functions, as well as specific effects on NK cell responses. Examination of NK cell cytotoxicity, blastogenesis, and IFN-gamma production demonstrated that: IL-12 was required for NK cell IFN-gamma production but not blastogenesis and cytotoxicity; IFN-alphabeta was necessary for NK cell blastogenesis and cytotoxicity but not IFN-gamma production; and TNF facilitated IFN-gamma production but inhibited NK cell cytotoxicity. This work defines the biologic consequences of early cytokine expression during viral infection.
426 citations
"Loss of mandibular lymph node integ..." refers background in this paper
...Regarding the innate immune response, IFN- promotes NK cell proliferation and cytotoxicity (42) in a STAT-4-independent, STAT-1-dependent fashion requiring IL-15 (43–45)....
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TL;DR: It is demonstrated that CD8+ T cells that are present in the TGs at the time of excision can maintain HSV-1 in a latent state in sensory neurons in ex vivo TG cultures, and it is proposed that when the intrinsic capacity of neurons to inhibit HSv-1 reactivation from latency is compromised, production of HSV -1 immediate early and early proteins might activate CD8- T cells aborting virion production.
Abstract: Recurrent herpes simplex virus type 1 (HSV-1) disease usually results from reactivation of latent virus in sensory neurons and transmission to peripheral sites. Therefore, defining the mechanisms that maintain HSV-1 in a latent state in sensory neurons may provide new approaches to reducing susceptibility to recurrent herpetic disease. After primary HSV-1 corneal infection, CD8+ T cells infiltrate the trigeminal ganglia (TGs) of mice, and are retained in latently infected ganglia. Here we demonstrate that CD8+ T cells that are present in the TGs at the time of excision can maintain HSV-1 in a latent state in sensory neurons in ex vivo TG cultures. Latently infected neurons expressed viral genome and some expressed HSV-1 immediate early and early proteins, but did not produce HSV-1 late proteins or infectious virions. Addition of anti-CD8α monoclonal antibody 5 d after culture initiation induced HSV-1 reactivation, as demonstrated by production of viral late proteins and infectious virions. Thus, CD8+ T cells can prevent HSV-1 reactivation without destroying the infected neurons. We propose that when the intrinsic capacity of neurons to inhibit HSV-1 reactivation from latency is compromised, production of HSV-1 immediate early and early proteins might activate CD8+ T cells aborting virion production.
396 citations
TL;DR: It is shown that the infected DC are defective in up‐regulating co‐stimulatory molecules, do not produce cytokines, and do not acquire responsiveness to chemokines required for migration to secondary lymphoid organs.
Abstract: Maturation of dendritic cells (DC), leading to migration and increased T cell stimulatory capacity, is essential for the initiation of immune responses. This process is triggered by a variety of stimuli, such as inflammatory cytokines, bacterial and viral products. Using a recombinant disabled infectious single cycle herpes simplex virus 1 (HSV-1) encoding green fluorescent protein, we show that the infected DC are defective in up-regulating co-stimulatory molecules, do not produce cytokines, and do not acquire responsiveness to chemokines required for migration to secondary lymphoid organs. These results reveal yet another strategy used by HSV-1 to evade the immune response, namely the inhibition of signaling pathways involved in DC maturation.
380 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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TL;DR: It is found that CD8+ T cell lytic granules are also required for the maintenance of neuronal latency both in vivo and in ex vivo ganglia cultures and that their directed release to the junction with neurons in latently infected ganglia did not induce neuronal apoptosis.
Abstract: Reactivation of herpes simplex virus type 1 (HSV-1) from neuronal latency is a common and potentially devastating cause of disease worldwide. CD8+ T cells can completely inhibit HSV reactivation in mice, with interferon-gamma affording a portion of this protection. We found that CD8+ T cell lytic granules are also required for the maintenance of neuronal latency both in vivo and in ex vivo ganglia cultures and that their directed release to the junction with neurons in latently infected ganglia did not induce neuronal apoptosis. Here, we describe a nonlethal mechanism of viral inactivation in which the lytic granule component, granzyme B, degrades the HSV-1 immediate early protein, ICP4, which is essential for further viral gene expression.
380 citations