The immune response to picornavirus infection and the effect of immune manipulation on acute seizures

DePaula-Silva, Ana Beatriz; Sonderegger, F. Lynn; Libbey, Jane E.; Doty, Daniel J.; Fujinami, Robert S.

doi:10.1007/s13365-018-0636-2

Cited by 22 publications

(38 citation statements)

References 46 publications

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“…This agrees with recent work by others investigating the role of microglia in CNS infection with TMEV (Waltl et al 2018b) and with the JHM strain of mouse hepatitis virus (JHMV), another neurotropic virus (Wheeler et al 2018). However, depletion of peripheral macrophages with clodronate-containing liposomes does not result in fatal encephalitis, but instead improves seizure outcomes (DePaula-Silva et al 2018;Waltl et al 2018a). In contrast, microglia-depleted mice maintain the development of seizures and go on to develop paralysis.…”

Section: Discussionsupporting

confidence: 91%

Microglial cell depletion is fatal with low level picornavirus infection of the central nervous system

et al. 2019

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Microglia are the only resident myeloid cell in the central nervous system (CNS) parenchyma, but the role of microglia in the context of neurotropic viral infection is poorly understood. Using different amounts of Theiler's murine encephalomyelitis virus (TMEV) in a preclinical model of epilepsy and PLX5622, a colony stimulating factor-1 receptor inhibitor that selectively depletes microglia in the CNS, we report that microglia-depleted, TMEV-infected mice develop seizures, manifest paralysis, and uniformly succumb to fatal encephalitis regardless of viral amount. CNS demyelination correlates with viral amount, however viral amount does not correlate with axon damage and TMEV antigen in the CNS.

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Section: Discussionsupporting

confidence: 91%

Microglial cell depletion is fatal with low level picornavirus infection of the central nervous system

et al. 2019

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“…Indeed, genetic deletion of either CD4 + or CD8 + cells from B6 mice resulted in viral persistence and demyelination during the chronic stage of disease (Murray et al, 1998). Interestingly, neither CD4 + nor CD8 + cells are required for development of acute seizures following infection with TMEV in B6 mice (DePaula-Silva et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

Microglia have a protective role in viral encephalitis-induced seizure development and hippocampal damage

Waltl

Käufer

Gerhauser

et al. 2018

Brain, Behavior, and Immunity

113

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In the central nervous system (CNS), innate immune surveillance is mainly coordinated by microglia. These CNS resident myeloid cells are assumed to help orchestrate the immune response against infections of the brain. However, their specific role in this process and their interactions with CNS infiltrating immune cells, such as blood-borne monocytes and T cells are only incompletely understood. The recent development of PLX5622, a specific inhibitor of colony-stimulating factor 1 receptor that depletes microglia, allows studying the role of microglia in conditions of brain injury such as viral encephalitis, the most common form of brain infection. Here we used this inhibitor in a model of viral infection-induced epilepsy, in which C57BL/6 mice are infected by a picornavirus (Theiler's murine encephalomyelitis virus) and display seizures and hippocampal damage. Our results show that microglia are required early after infection to limit virus distribution and persistence, most likely by modulating T cell activation. Microglia depletion accelerated the occurrence of seizures, exacerbated hippocampal damage, and led to neurodegeneration in the spinal cord, which is normally not observed in this mouse strain. This study enhances our understanding of the role of microglia in viral encephalitis and adds to the concept of microglia-T cell crosstalk.

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“…As components of the innate immune response, microglia and macrophages are frequently associated with CNS pathologies such as neuroinflammation. The presence of reactive microglia and infiltration of macrophages into the CNS are often observed during brain inflammation (encephalitis), Parkinson's disease, multiple sclerosis, traumatic brain injury, and brain tumorigenesis, among others [15,[20][21][22][23][24][25]. Upon activation, macrophages can acquire distinct phenotypes such as the classically defined M1, or proinflammatory, and M2, or anti-inflammatory, polarization states.…”

Section: Introductionmentioning

confidence: 99%

“…These acute seizures are characterized by CNS infiltration of immune cells such as macrophages and lymphocytes [15,[34][35][36]. We have previously determined that macrophage infiltration, more specifically IL-6-producing macrophages [15,22,35,36], but not T cell or neutrophil infiltration, is important for seizure development [22]. Recently, we and others have also demonstrated that macrophages and microglia have unique roles in controlling viral infection in the brain [37][38][39].…”

Section: Introductionmentioning

confidence: 99%

Differential transcriptional profiles identify microglial- and macrophage-specific gene markers expressed during virus-induced neuroinflammation

DePaula-Silva

Gorbea

Doty

et al. 2019

J Neuroinflammation

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105

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Background In the healthy central nervous system (CNS), microglia are found in a homeostatic state and peripheral macrophages are absent from the brain. Microglia play key roles in maintaining CNS homeostasis and acting as first responders to infection and inflammation, and peripheral macrophages infiltrate the CNS during neuroinflammation. Due to their distinct origins and functions, discrimination between these cell populations is essential to the comprehension of neuroinflammatory disorders. Studies comparing the gene profiles of microglia and peripheral macrophages, or macrophages in vitro-derived from bone marrow, under non-infectious conditions of the CNS, have revealed valuable microglial-specific genes. However, studies comparing gene profiles between CNS-infiltrating macrophages and microglia, when both are isolated from the CNS during viral-induced neuroinflammation, are lacking. Methods We isolated, via flow cytometry, microglia and infiltrating macrophages from the brains of Theiler’s murine encephalomyelitis virus-infected C57BL/6 J mice and used RNA-Seq, followed by validation with qPCR, to examine the differential transcriptional profiles of these cells. We utilized primary literature defining subcellular localization to determine whether or not particular proteins extracted from the transcriptional profiles were expressed at the cell surface. The surface expression and cellular specificity of triggering receptor expressed on myeloid cells 1 (TREM-1) protein were examined via flow cytometry. We also examined the immune response gene profile within the transcriptional profiles of these isolated microglia and infiltrating macrophages. Results We have identified and validated new microglial- and macrophage-specific genes, encoding cell surface proteins, expressed at the peak of neuroinflammation. TREM-1 protein was confirmed to be expressed by infiltrating macrophages, not microglia, at the peak of neuroinflammation. We also identified both unique and redundant immune functions, through examination of the immune response gene profiles, of microglia and infiltrating macrophages during neurotropic viral infection. Conclusions The differential expression of cell surface-specific genes during neuroinflammation can potentially be used to discriminate between microglia and macrophages as well as provide a resource that can be further utilized to target and manipulate specific cell responses during neuroinflammation. Electronic supplementary material The online version of this article (10.1186/s12974-019-1545-x) contains supplementary material, which is available to authorized users.

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The immune response to picornavirus infection and the effect of immune manipulation on acute seizures

Cited by 22 publications

References 46 publications

Microglial cell depletion is fatal with low level picornavirus infection of the central nervous system

Microglial cell depletion is fatal with low level picornavirus infection of the central nervous system

Microglia have a protective role in viral encephalitis-induced seizure development and hippocampal damage

Differential transcriptional profiles identify microglial- and macrophage-specific gene markers expressed during virus-induced neuroinflammation

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