Pharmacologic Depletion of Microglia Increases Viral Load in the Brain and Enhances Mortality in Murine Models of Flavivirus-Induced Encephalitis

Seitz, Scott; Clarke, Penny; Tyler, Kenneth L.

doi:10.1128/jvi.00525-18

Cited by 75 publications

(98 citation statements)

References 46 publications

(53 reference statements)

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“…The early inflammasome activation of microglia appears to be an important general mechanism of infection control in the CNS. There is agreement between studies, that microglia depletion by pharmacological inhibition of the CSF‐R1 exacerbates disease in diverse models of virus infection of the brain (Sanchez et al, ; Seitz, Clarke, & Tyler, ; Waltl et al, ; Wheeler & Quintana, ). This may be due to a role of microglia in the local restimulation of CD8 + T‐cells (Funk & Klein, ).…”

Section: Microglia and Macrophages In Inflammatory Diseases In Humansmentioning

confidence: 80%

Pathology of inflammatory diseases of the nervous system: Human disease versus animal models

Lassmann

2019

Glia

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Numerous recent studies have been performed to elucidate the function of microglia, macrophages, and astrocytes in inflammatory diseases of the central nervous system. Regarding myeloid cells a core pattern of activation has been identified, starting with the activation of resident homeostatic microglia followed by recruitment of blood borne myeloid cells. An initial state of proinflammatory activation is at later stages followed by a shift toward an‐anti‐inflammatory and repair promoting phenotype. Although this core pattern is similar between experimental models and inflammatory conditions in the human brain, there are important differences. Even in the normal human brain a preactivated microglia phenotype is evident, and there are disease specific and lesion stage specific differences in the contribution between resident and recruited myeloid cells and their lesion state specific activation profiles. Reasons for these findings reside in species related differences and in differential exposure to different environmental cues. Most importantly, however, experimental rodent studies on brain inflammation are mainly focused on autoimmune encephalomyelitis, while there is a very broad spectrum of human inflammatory diseases of the central nervous system, triggered and propagated by a variety of different immune mechanisms.

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Section: Microglia and Macrophages In Inflammatory Diseases In Humansmentioning

confidence: 80%

Pathology of inflammatory diseases of the nervous system: Human disease versus animal models

Lassmann

2019

Glia

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“…In a recent study using PLX5622 for determining the role of microglia in flaviviral pathogenesis in female Swiss-Webster mice (Seitz et al, 2018), depletion of microglia resulted in increased mortality and viral titer in the brain following infection with either West Nile virus (WNV) or Japanese encephalitis virus (JEV). Interestingly, the expression of several pro-inflammatory genes was increased in virus-infected, microglial-depleted mice compared to virus-infected, untreated controls.…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, the expression of several pro-inflammatory genes was increased in virus-infected, microglial-depleted mice compared to virus-infected, untreated controls. T cell responses were not examined in the study of Seitz et al (2018).…”

Section: Discussionmentioning

confidence: 99%

“…Recently, a new compound, PLX5622, which acts as specific dietary inhibitor of colony stimulating factor-1 receptor (CSF1R), a tyrosine kinase transmembrane receptor essential for the survival and activation of monocytes and macrophages in the periphery and microglia in the CNS (Erblich et al, 2011;Hamilton and Achuthan, 2013;Elmore et al, 2014), was shown to efficiently eliminate microglia in mice (Dagher et al, 2015). Similar to the less specific CSF1R inhibitor PLX3397 , PLX5622 has been used to study the role of microglia in several conditions of brain injury (Acharya et al, 2016;Feng reported that microglia depletion by PLX5622 increases virus replication and subsequent mortality in response to intracerebral infection with mouse hepatitis virus (MHV; Wheeler et al, 2018) or flaviviruses (West Nile virus and Japanese encephalitis virus; Seitz et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

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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 suggested in the present study, the inappropriate recruitment or retention of immune cells within the CNS may have detrimental effects. Depletion of microglia has been shown to result in increased mortality and viral titre in the brain following WNV subcutaneous infection without showing differences between CCL2, CCL5 or CXCL10 RNA expression, pointing out to a protective role of resident microglia against viral damage (Seitz, Clarke, & Tyler, ). Accordingly, our results have not pointed to microglia as main sources of these chemokines after WNV infection.…”

Section: Discussionmentioning

confidence: 99%

West Nile Virus spread and differential chemokine response in the central nervous system of mice: Role in pathogenic mechanisms of encephalitis

Vidaña

Johnson

Fooks

et al. 2019

Transbound Emerg Dis

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Summary West Nile virus (WNV) is a zoonotic mosquito‐borne flavivirus able to cause severe neurological disease in humans, horses and various avian species. The more severe pathological changes of neurotropic WNV infection are caused by virus neuroinvasion and/or the immunological response in the central nervous system (CNS). The extent in which inflammatory cell trafficking orchestrated by chemokines is involved in the pathogenesis of CNS lesions has not been entirely elucidated. To understand the sequence of pro‐inflammatory chemokine induction during WNV encephalitis, a murine intranasal inoculation model was used. The relationship between lesional patterns in the mice CNS, the viral antigen distribution and the expression of pro‐inflammatory chemokine (CCL2, CCL5 and CXCL10) were evaluated. Viral antigen was first observed in olfactory tract and pyriform cortex neurons, suggesting a retrograde neuronal infection from the olfactory nerve. A spatio‐temporal association between WNV antigen and perivascular cuffs development was observed. Chemokine immunostaining was widely distributed in the brain from early stages. CCL2 immunolabelling was localised in neurons, astrocytes, microglia and endothelial cells as well as mononuclear leucocytes within perivascular cuffs. In contrast, CCL5 and CXCL10 immunostaining were mainly observed in astroglia and neurons, respectively. A strong correlation was demonstrated between the presence of perivascular cuffs and CCL2 and CCL5 expression in most brain areas, while CXCL10 was only associated with inflammatory lesions in few specific regions. Importantly, a strong correlation between WNV and CCL5 distribution was observed. However, no correlation was observed between CXCL10 and viral antigen. Neurons were confirmed as the main target cells of WNV, as well as one of the sources of CCL2, CCL5 and CXCL10. This study shows the sequence and comparative distribution pattern between histological lesions, WNV antigen and chemokine expression over the infection process. Furthermore, it identifies potential targets for immune intervention to suppress damaging chemokine responses.

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Pharmacologic Depletion of Microglia Increases Viral Load in the Brain and Enhances Mortality in Murine Models of Flavivirus-Induced Encephalitis

Cited by 75 publications

References 46 publications

Pathology of inflammatory diseases of the nervous system: Human disease versus animal models

Pathology of inflammatory diseases of the nervous system: Human disease versus animal models

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

West Nile Virus spread and differential chemokine response in the central nervous system of mice: Role in pathogenic mechanisms of encephalitis

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