Immunopathogenesis of Acute Central Nervous System Disease Produced by Lymphocytic Choriomeningitis Virus

Gilden, Donald H.; Cole, Gerald A.; Monjan, Andrew A.; Nathanson, Neal

doi:10.1084/jem.135.4.860

Cited by 122 publications

(51 citation statements)

References 22 publications

(22 reference statements)

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“…The nearly normal type I IFN response in the CNS of IRF7 Ϫ/Ϫ mice therefore suggests that inside the CNS, non-pDCs would dominate as producers of type I IFNs. Consistent with this hypothesis, we found that most cells taking part in the early type I IFN response in the LCMV-infected CNS are the parenchymal CNS cells next to the injection site and the cells forming the meningeal and ependymal linings; this is not surprising and is in full agreement with the distribution of virus-infected cells at this time (11,17). The type I IFN response increases over time (8,50), and with time, GFAP ϩ astrocytes and recruited CD3 ϩ cells were also found to produce type I IFN, which is in agreement with previous findings showing that astrocytes (44) and murine T cells (29) are able to produce IFN-␤.…”

Section: Discussionsupporting

confidence: 77%

Differential Impact of Interferon Regulatory Factor 7 in Initiation of the Type I Interferon Response in the Lymphocytic Choriomeningitis Virus-Infected Central Nervous System versus the Periphery

Christensen¹,

Fenger

Issazadeh‐Navikas

et al. 2012

J Virol

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g Interferon (IFN) regulatory factors (IRFs) are a family of transcription factors involved in regulating type I IFN genes and other genes participating in the early antiviral host response. To better understand the mechanisms involved in virus-induced central nervous system (CNS) inflammation, we studied the influence of IRF1, -3, -7, and -9 on the transcriptional activity of key genes encoding antiviral host factors in the CNS of mice infected with lymphocytic choriomeningitis virus (LCMV). A key finding is that neither IRF3 nor IRF7 is absolutely required for induction of a type I IFN response in the LCMV-infected CNS, whereas concurrent elimination of both factors markedly reduces the virus-induced host response. This is unlike the situation in the periphery, where deficiency of IRF7 almost eliminates the LCMV-induced production of the type I IFNs. This difference is seemingly related to the local environment, as peripheral production of type I IFNs is severely reduced in intracerebrally (i.c.) infected IRF7-deficient mice, which undergo a combined infection of the CNS and peripheral organs, such as spleen and lymph nodes. Interestingly, despite the redundancy of IRF7 in initiating the type I IFN response in the CNS, the response is not abolished in IFN-␤-deficient mice, as might have been expected. Collectively, these data demonstrate that the early type I IFN response to LCMV infection in the CNS is controlled by a concerted action of IRF3 and -7. Consequently this work provides strong evidence for differential regulation of the type I IFN response in the CNS versus the periphery during viral infection.T ype I interferons (IFNs) (predominantly IFN-␣/␤) are among the earliest cytokines to be produced in the innate host response to a viral infection. The initiation of this response relies on the sensing of viral invasion by different types of cellular pathogen-recognizing receptors (PRRs) (26, 38). They include several of the Toll-like receptors (TLRs), together with an increasing number of cytosolic receptors detecting nucleic acid sequences indicative of viral presence within the host cell (24,26,27,30,38,41,49,56,59). Upon engagement of the relevant PRRs, several transcription factors, including interferon regulatory factors (IRFs), activator protein 1 (AP-1), and NF-B, are activated and translocated into the nucleus to induce the expression of proinflammatory cytokines and type I IFNs. Induction of a broad range of type I IFNs and IFN-stimulated genes (ISGs) involves several members of the IRF family. In fibroblasts and epithelial cells, the production of type I IFNs is biphasic, and in the earliest response, phosphorylation of IRF3 leads to the production of small amounts of 51). The secreted IFNs act in a paracrine/autocrine manner with locally expressed type I IFN receptors (IFNARs), and this interaction causes several important secondary response molecules, including IRF7, to become upregulated in the type I IFN-exposed cells. As a result of IRF7 induction, the expression of all type I IFN species is...

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Section: Discussionsupporting

confidence: 77%

Differential Impact of Interferon Regulatory Factor 7 in Initiation of the Type I Interferon Response in the Lymphocytic Choriomeningitis Virus-Infected Central Nervous System versus the Periphery

Christensen¹,

Fenger

Issazadeh‐Navikas

et al. 2012

J Virol

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“…Non-barrier maintained mouse colonies are almost universally contaminated with viral pathogens that have the potential to influence immune responses (19,20), induce autoantibodies (21), increase mortality in aging mice (22), directly infect the central nervous system (23)(24)(25)(26)(27)(28), and cause paralysis (23)(24)(25)28). We therefore employed a protocol that ensured that our mice were not infected with specific pathogens.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of memory, learning ability, and clinical neurologic function in pathogen‐free mice with systemic lupus erythematosus

Vogelweid

Wright

Johnson

et al. 1994

Arthritis & Rheumatism

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Objective. To determine if neurologic impairment is related to progressive autoimmune disease in 3 murine models of systemic lupus erythematosus (SLE): MRLl lpr, NZB, and NZBIWF,.Methods. Sensorimotor function, learning, and memory were tested within strains at specific ages, before and after the appearance of SLE. These parameters were also compared between strains for young and older lupus mice and their congenic controls with reduced autoimmune disease (MRL/lpr versus MRL/+ ; NZB versus NZB/xid).Results. Abnormal neurologic features were present at a much higher frequency in MRL/lpr mice than in age-matched MRL/+ control mice, and sensorimotor function deficits were also seen in NZB/WF, mice. Strains that develop lupus showed deficits on a waterescape, distal cue discrimination task and on a foodrewarded, proximal cue discrimination task, but the cognitive impairments were not global.Conclusion. MRL/lpr, NZB, and NZB/WF, mice differed in terms of which behaviors were impaired as well as when those impairments appeared.Abnormalities of neurologic and cognitive function are second only to renal disease in producing

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“…This explanation is consistent with a wealth of literature demonstrating that the fatal outcome of LCMV-induced meningitis is solely dependent on the rapid recruitment of CD8 ϩ effector T cells to sites of virus replication in the CNS. Thus, partial suppression of the virus-specific CD8 ϩ T-cell response by pharmacological inhibitors or the inoculation of a relatively high virus dose usually does not result in fatal meningitis but rather slows the recruitment of CD8 ϩ T cells to the CNS, allowing viral clearance to proceed normally (22,25).…”

Section: Cd8mentioning

confidence: 99%

Regulation of Immune Response and Inflammatory Reactions against Viral Infection by VCAM-1

Zhang

Huang

et al. 2008

J Virol

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The migration of activated antigen-specific immune cells to the target tissues of virus replication is controlled by the expression of adhesion molecules on the vascular endothelium that bind to ligands on circulating lymphocytes. Here, we demonstrate that the adhesion pathway mediated by vascular cell adhesion molecule 1 (VCAM-1) plays a role in regulating T-cell-mediated inflammation and pathology in nonlymphoid tissues, including the central nervous system (CNS) during viral infection. The ablation of VCAM-1 expression from endothelial and hematopoietic cells using a loxP-Cre recombination strategy had no major effect on the induction or overall tissue distribution of antigen-specific T cells during a systemic infection with lymphocytic choriomeningitis virus (LCMV), except in the case of lung tissue. However, enhanced resistance to lethal LCM and the significantly reduced magnitude and duration of footpad swelling observed in VCAM-1 mutant mice compared to B6 controls suggest a significant role for VCAM-1 in promoting successful local inflammatory reactions associated with efficient viral clearance and even life-threatening immunopathology under particular infection conditions. Interestingly, analysis of the infiltrating populations in the brains of intracerebrally infected mice revealed that VCAM-1 deletion significantly delayed migration into the CNS of antigen-presenting cells (macrophages and dendritic cells), which are critical for optimal stimulation of migrating virusspecific CD8؉ T cells initiating a pathological cascade. We propose that the impaired migration of these accessory cells in the brain may explain the improved clinical outcome of infection in VCAM-1 mutant mice. Thus, these results underscore the potential role of VCAM-1 in regulating the immune response and inflammatory reactions against viral infections.

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Immunopathogenesis of Acute Central Nervous System Disease Produced by Lymphocytic Choriomeningitis Virus

Cited by 122 publications

References 22 publications

Differential Impact of Interferon Regulatory Factor 7 in Initiation of the Type I Interferon Response in the Lymphocytic Choriomeningitis Virus-Infected Central Nervous System versus the Periphery

Differential Impact of Interferon Regulatory Factor 7 in Initiation of the Type I Interferon Response in the Lymphocytic Choriomeningitis Virus-Infected Central Nervous System versus the Periphery

Evaluation of memory, learning ability, and clinical neurologic function in pathogen‐free mice with systemic lupus erythematosus

Regulation of Immune Response and Inflammatory Reactions against Viral Infection by VCAM-1

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